Journal articles on the topic 'IL1RL1 (ST2)'
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Ramirez-Carrozzi, Vladimir, Amy Dressen, Patrick Lupardus, Brian Yaspan, and Rajita Pappu. "Functional analysis of protective IL1RL1 variants associated with asthma risk (CCR6P.215)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 187.2. http://dx.doi.org/10.4049/jimmunol.194.supp.187.2.
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Abstract GWAS studies have identified polymorphisms in both IL33 and IL1RL1, the gene encoding ST2, the high affinity chain of the IL-33 receptor, that associate with asthma susceptibility. We identified amino acid changing variants in IL1RL1 associating with asthma incidence and found these SNPs to be protective from asthma risk in our study population. These variants result in coding changes to the intracellular region of ST2, which contains the TIR domain of the receptor that is critical for signaling downstream of IL-1 cytokine family and TLRs. Mutations or deletions to this region can inhibit ligand-induced responses. IL-33-mediated dimerization of ST2 and IL-1RAcP promotes TIR-TIR domain interaction and recruitment of the adaptor molecule MyD88 leading to AP-1 and NF-kB activation. IL-33 responses were diminished in cell lines expressing all 4 IL1RL1 missense variants. To further elucidate how this haplotype could affect IL-33 activity, we compared IL-33 activity and ST2 expression between donors carrying either haplotype. We observed reduced IL-33 mediated IL-8 secretion from purified blood eosinophils derived from individuals carrying the protective haplotype. We also observed greater soluble ST2 expression in these individuals. Our results provide a link between the genetic predisposition to asthma and IL-33 mediated responses. Given IL-33 promotes Th2 immunity, perturbations that diminish this response may provide protection from asthma risk.
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Dale, Mark, and Martin J. H. Nicklin. "Interleukin-1 Receptor Cluster: Gene Organization ofIL1R2, IL1R1, IL1RL2(IL-1Rrp2),IL1RL1(T1/ST2), andIL18R1(IL-1Rrp) on Human Chromosome 2q." Genomics 57, no. 1 (April 1999): 177–79. http://dx.doi.org/10.1006/geno.1999.5767.
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Ho, Jennifer E., Wei-Yu Chen, Ming-Huei Chen, Martin G. Larson, Elizabeth L. McCabe, Susan Cheng, Anahita Ghorbani, et al. "Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling." Journal of Clinical Investigation 123, no. 10 (September 3, 2013): 4208–18. http://dx.doi.org/10.1172/jci67119.
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Valeff, Natalin Jimena, Maria Silvia Ventimiglia, Florencia Quadrana, and Federico Jensen. "ST2-expressing B1 B cells acquire an anti-inflammatory capacity during pregnancy in mice." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 235.14. http://dx.doi.org/10.4049/jimmunol.204.supp.235.14.
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Abstract In the context of pregnancy, it is known that IL-33 induces the production of anti-inflammatory molecules by decidual B1 cells, protecting against preterm birth (PTB) in human and mouse. We have previously showed that expression of IL-33 receptor, Il1rl1 (ST2) is significantly upregulated in splenic B cells during mid pregnancy, predominantly in B1 cell subset. Furthermore, using an LPS induced PTB mouse model, we observed increased numbers of splenic and decidual ST2-expressing B1 cells in the acute phase of PTB as compared to term pregnant females. We aimed to investigate here the anti-inflammatory properties of ST2-expressing B1 cells during pregnancy. Total splenocytes from pregnant (P) and non-pregnant (NP) mice were isolated and cultured for 24h with/without LPS (10 μgr/ml), ST2 expression and cytokine production by ST2+ B1 cells was evaluated by flow cytometry. B1 cells from P mice stimulated with LPS showed significantly higher levels of ST2 expression. ST2+ B1 cells produced significantly higher levels of IL-10 and significantly lower levels of TNF-α and IL-17 as compared to ST2+ B1 cells from NP mice. In a separate project in our laboratory we demonstrated that prophylactic treatment with probiotic Lactobacillus kefiri prevented LPS-induced PTB in mice. Interestingly, we observed that numbers of splenic and decidual ST2-expressing B1 cells were increased in L. kefiri treated mice that were protected against LPS-induced PTB. Our data strongly suggest an anti-inflammatory capacity of ST2-expressing B1 cells during gestation, presumably to ensure pregnancy wellbeing and prevent inflammation induced PTB.
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Rasheed, Kashif, Ugo Moens, Benedetta Policastro, John Inge Johnsen, Virve Koljonen, Harri Sihto, Weng-Onn Lui, and Baldur Sveinbjørnsson. "The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma." International Journal of Molecular Sciences 23, no. 7 (March 28, 2022): 3702. http://dx.doi.org/10.3390/ijms23073702.
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Merkel cell polyomavirus (MCPyV) is a causal factor in Merkel cell carcinoma (MCC). The oncogenic potential is mediated through its viral oncoproteins large T-antigen (LT) and small T-antigen (sT). Cytokines produced by tumor cells play an important role in cancer pathogenesis, and viruses affect their expression. Therefore, we compared human cytokine and receptor transcript levels in virus positive (V+) and virus negative (V−) MCC cell lines. Increased expression of IL-33, a potent modulator of tumor microenvironment, was observed in V+ MCC cell lines when compared to V− MCC-13 cells. Transient transfection studies with luciferase reporter plasmids demonstrated that LT and sT stimulated IL-33, ST2/IL1RL1 and IL1RAcP promoter activity. The induction of IL-33 expression was confirmed by transfecting MCC-13 cells with MCPyV LT. Furthermore, recombinant human cytokine domain IL-33 induced activation of MAP kinase and NF-κB pathways, which could be blocked by a ST2 receptor antibody. Immunohistochemical analysis demonstrated a significantly stronger IL-33, ST2, and IL1RAcP expression in MCC tissues compared to normal skin. Of interest, significantly higher IL-33 and IL1RAcP protein levels were observed in MCC patient plasma compared to plasma from healthy controls. Previous studies have demonstrated the implication of the IL-33/STL2 pathway in cancer. Because our results revealed a T-antigens-dependent induction of the IL-33/ST2 axis, IL-33/ST2 may play a role in the tumorigenesis of MCPyV-positive MCC. Therefore, neutralizing the IL-33/ST2 axis may present a novel therapeutic approach for MCC patients.
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Griesenauer, Brad, Jilu Zhang, Abdulraouf M. Ramadan, and Sophie Paczesny. "Deficiency of MyD88 signaling in CD4 Tconvs increases Tregs suppression through loss of ST2 signaling." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 82.12. http://dx.doi.org/10.4049/jimmunol.198.supp.82.12.
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Abstract Acute graft-versus-host disease (aGVHD) hinders the efficacy of allogeneic hematopoietic cell transplantation (allo-HCT). We found that plasma soluble suppression of tumorigenicity 2 (sST2) predicted GVHD-related mortality in allo-HCT patients. ST2 signals through the adapter protein MyD88. Lack of MyD88 in CD4 Tconvs has been shown to decrease ovalbumin or a peptide to the haplotype H2b stimulated Th1/Th17 cells via the IL-1R. Thus, we hypothesized that absence of MyD88 signaling would protect against aGVHD through IL-1R, ST2, or both. We found that knocking out MyD88 in the donor T cells protected against aGVHD while recipients of IL-1R−/− donor T cells showed no difference. We found that the aGVHD protection was entirely driven by MyD88−/− CD4 T cells. There were no differences in proliferation, apoptosis, or migration in WT or MyD88−/− CD4 T cells. We next explored the cell-intrinsic role of MyD88−/− Tconvs and Tregs. We did not find a difference in survival in aGVHD models with MyD88−/− Tconvs or MyD88−/− Tregs. However, use of MyD88−/− Tconvs with WT or MyD88−/− Tregs ameliorated aGVHD. We hypothesized that this was mediated by lack of ST2 on donor Tconvs. Recipients of ST2−/− Tconvs with WT or ST2−/− Tregs lowered aGVHD mortality, mirroring MyD88−/− Tconvs. Transcriptome analysis comparing 10 days post-HCT CD4 T cells from MyD88−/− versus WT recipients showed lower levels of Irak1, Il1rl1 (gene of ST2), Ifng, Csf2, Stat5, and Jak2 as well as decreased systemic plasma sST2 and IFN-γ levels. Our data suggests that Tregs suppression from lack of MyD88 signaling in Tconvs during alloreactivity uses the ST2 but not the IL-1R pathway, possibly by different antigen stimulation. MyD88 represents an aGVHD therapeutic target sparing Treg function.
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Tago, Kenji, Satoshi Ohta, Megumi Funakoshi-Tago, Chihiro Aoki-Ohmura, Jitsuhiro Matsugi, Shin-ichi Tominaga, and Ken Yanagisawa. "STAT3 and ERK pathways are involved in cell growth stimulation of the ST2/IL1RL1 promoter." FEBS Open Bio 7, no. 2 (January 19, 2017): 293–302. http://dx.doi.org/10.1002/2211-5463.12192.
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Bahrij, D. A. "Clinical significance of single nucleotide missense-mutation rs950880 of the IL1RL1 gene in patients with essential hypertension." Biomedical and Biosocial Anthropology, no. 42 (March 27, 2021): 52–56. http://dx.doi.org/10.31393/bba42-2021-09.
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Modern cardiology requires the search for specific pathogenetically involved gene mutations, the consequences of which can be considered in the management of patients with hypertension. Scientists are targeting C/A polymorphism at the rs950880 position, which is associated with tissue expression of the IL1RL1 gene and the plasma level of soluble ST2 – a new biomarker in the diagnosis of cardiovascular disease. The aim of the study was to evaluate the association of rs950880 polymorphism of the IL1RL1 gene and the state of central and intracardiac hemodynamics in men with essential hypertension (EН) of varying severity, residents of the Podillia region of Ukraine. 170 men who met the inclusion criteria were examined according to a standard protocol, which included clinical, laboratory and instrumental examinations in accordance with current recommendations. The subjects were divided into a control group of 70 men without cardiovascular disease and a study group of 50 men with asymptomatic EН and 50 people with EH complicated by IIA stage chronic heart failure (CHF). Genotyping of SNP rs950880 of the IL1RL1 gene was performed using an allele-specific polymerase chain reaction. All men in the control group and the study group underwent echocardiography with Doppler according to the standard protocol. Statistical processing of the obtained results was performed in the package Statistica 12.0 using conjugation tables analysis, analysis of variance. It was found that among men living in Vinnytsia, Ukraine, carriers of СС and CA SNP rs950880 of the IL1RL1 gene dominate (42.35 % and 45.30 % of individuals, respectively), AA homozygotes are significantly less common (12.53 %, p<0.05). Men without cardiovascular diseases and patients with EH do not differ significantly in the frequency of different variants of the genotype of the studied gene. C\A polymorphism is not associated with the risk of EН. The homozygotes AA with EH have a significantly lower LV myocardial mass index (LVMMI) (69.14±6.90 g/m2.7, compared with homozygotes CC – 75.42±2.54 g/m2.7, and heterozygotes CA – 76.96±3.18 g/m2.7, p<0.05). Among the carriers of the C allele, an "unfavorable" EН phenotype is mainly formed in the form of a high risk of LV hypertrophy (OR=11.36, 95 % СI=0.63-24.76, χ2=14.32, p=0.0008). Homozygotes AA in the rs950880 locus of the IL1RL1 gene, on the contrary, have a low probability of developing LV hypertrophy (OR=0.80, 95 % SI=0.02-0.42, χ2=14.32, p=0.0008) and its preserved systolic function. Thus, the SNP rs950880 of the IL1RL1 gene is not associated with the risk of EH or its severity in residents of Vinnytsia, Ukraine. Carriage of the C allele is accompanied by the formation of an "unfavorable" EH phenotype with a significantly high risk of LV hypertrophy.
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Baba, Yosuke, Keiko Maeda, Takuya Yashiro, Eisuke Inage, Frangois Niyonsaba, Mutsuko Hara, Ryuyo Suzuki, et al. "Involvement of PU.1 in Mast Cell/Basophil-Specific Function of the Human IL1RL1/ST2 Promoter." Allergology International 61, no. 3 (2012): 461–67. http://dx.doi.org/10.2332/allergolint.12-oa-0424.
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Maywald, Rebecca L., Stephanie K. Doerner, Luca Pastorelli, Carlo De Salvo, Susan M. Benton, Emily P. Dawson, Denise G. Lanza, et al. "IL-33 activates tumor stroma to promote intestinal polyposis." Proceedings of the National Academy of Sciences 112, no. 19 (April 27, 2015): E2487—E2496. http://dx.doi.org/10.1073/pnas.1422445112.
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Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the ApcMin/+ mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in ApcMin/+ polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in ApcMin/+ polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.
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Queiroz, Gerson Almeida, Ryan Santos Costa, Valdirene Leao Carneiro, Talita Santos Jesus, Neuza Maria Alcântara-Neves, Anaque Oliveira Pires, Héllen Freitas Fonseca, Mauricio Lima Barreto, and Camila Alexandrina Figueiredo. "IL1RL1 Variants rs1041973 and rs873022 are Associated With Allergy Markers and Soluble ST2 Production in a Brazilian Population." Journal of Allergy and Clinical Immunology 139, no. 2 (February 2017): AB4. http://dx.doi.org/10.1016/j.jaci.2016.12.067.
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Karaesmen, Ezgi, Theresa E. Hahn, Alexander Dile, Abbas Rizvi, Junke Wang, Tao Wang, Michael D. Haagenson, et al. "Multiple Functional Donor Polymorphisms in IL1RL1 region Associate with Death Due to GvHD or Infection after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for AML and MDS." Blood 132, Supplement 1 (November 29, 2018): 312. http://dx.doi.org/10.1182/blood-2018-99-115276.
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Abstract The last two authors contributed equally Elevated soluble Stimulation-2 (sST2), the decoy IL-33 receptor, in plasma/serum post-HSCT is a biomarker for death due to GvHD. ST2 is the product of IL1RL1 (2q12.1) and this ~.5Mb region contains >300 single nucleotide polymorphisms (SNPs) significantly associated (P<5x10-8) with plasma levels of sST2 in healthy participants from the Framingham Heart Study (FHS). Many of these SNPs are genome-wide associated with infection-related phenotypes, including asthma, Crohn's disease, ulcerative colitis and celiac disease. Given these relationships, we analyzed the association of ST2 SNPs with death due to GvHD or infection within one year after HLA-matched unrelated donor HCT for AML or MDS to identify functional SNPs that could potentially aid in donor selection. We measured plasma/serum sST2 levels in pre-HCT samples in a subset of AML and MDS patients (n=759) and their donors (n=757) from DISCOVeRY-BMT, a GWAS of >3,000 recipient-unrelated donor pairs reported to the CIBMTR between 2000-2011. After quality control (info>.8, MAF>.005), 3613 SNPs in the IL1RL1 region were tested for association with sST2 levels; 1541 donor SNPs associated with sST2 levels (P<.05), which validated 99% of the FHS sST2 SNP associations. To assess the contribution of these donor variants to post-HCT survival, we constructed competing risk models with clinical variables using stepwise Akaike Information Criterion (AIC), then tested each of the 1541 donor SNPs for association with each outcome in the two DISCOVeRY-BMT cohorts. Causes of death were previously adjudicated by a multi-member panel. Meta-analyses of the two cohorts identified 13 GvHD-death associated SNPs and 118 infection-death associated SNPs. Sensitivity analyses show 91/118 SNPs are still significant after excluding patients with a history of acute GvHD grade III-IV (Figure 1). When taking correlations into account, we found 10 and three independent SNPs (R2<.6) associate with death due to infection and GvHD, respectively. There were no overlapping SNP associations between GvHD-death or infection-death (Figure 1). For GvHD-death associated SNPs, alleles associated with higher sST2 levels associate with increased risk for GvHD-death, while for infection-death SNPs, alleles associated with higher sST2 levels reduced risk of infection-death. AIC multivariable models for GvHD-death included AML diagnosis, recipient obesity (>30 mg/kg2), peripheral blood cell source, donor age, rs1558645 (Pmeta=.001), and rs2310241(Pmeta=.0003), for which the risk alleles at each SNP increased risk of GvHD death ~1.5 fold. The model for infection-death included advanced disease at HCT, recipient/donor CMV status, peripheral blood cell source, rs13019803 (Pmeta=1.1 x 10-6), rs13015714 (Pmeta=5 x 10-4) and rs4851601 (Pmeta=2 x 10-6), with risk alleles at each SNP increasing risk of infection-death ~2-fold. To capture the total contribution of these donor variants to each outcome we created multi-allele models for GvHD-death (0-4 alleles) and infection-death (0-6 alleles).The multi-allele GvHD models showed a 1.5 fold increased risk of GvHD-death with each additional allele (Pmeta=3.4 x 10-6 ) (Figure 2). Individuals whose donors are homozygous for both risk alleles at each SNP have a ~3 fold, and ~2 fold higher risk of dying of GvHD versus those with zero, and 1-2 risk allele(s), respectively. The multi-allele infection models (0-6 alleles) show a ~2 fold increased risk of infection-death (Pmeta= 1.22 x 10-10) with each risk allele (Figure 2). sST2 is one of the most reproducible GvHD biomarkers to date. As hypothesized, specific alleles correlated with high sST2 levels in donors and with GvHD-death. Our novel finding is that some ST2 alleles associated with low sST2 levels correlated with infection-death. These results are not without precedent, for example the low-sST2 associated allele in rs13019803 (T) associates with higher mortality in the CHARGE consortium. The risk allele in rs13015714 (T) is significantly associated with lower IL1RL1 and IL18R1 (P= 5 x 10-10) gene expression in lung tissue, indicating biochemical functions for these SNPs. Importantly the non-risk allele in all 5 variants are common (>20%) across races and ethnicities, which means there is an opportunity to select donors without combinations of these variants and perhaps without the requirement of measuring the protein level pre-transplant. Disclosures McCarthy: Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Lee:Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding; Takeda: Research Funding. Paczesny:Viracor IBT Laboratories: Patents & Royalties.
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Fu, Denggang, Hua Jiang, Alan Long, Hong fen Guo, Maegan L. Capitano, Baskar Ramdas, Reuben Kapur, Nai-Kong V. Cheung, and Sophie Paczesny. "Immunotherapy Targeting ST2/IL-33 Signaling in Myeloid Leukemia Stem Cells." Blood 138, Supplement 1 (November 5, 2021): 23. http://dx.doi.org/10.1182/blood-2021-149672.
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Abstract Therapies for acute myeloid leukemia (AML) has barely changed over 30 years, while treatment for other blood cancers have made remarkable leaps forward. Recent advances in genomics have allowed molecular targeted therapies (i.e. FLT3-ITD, IDH, c-KIT inhibitors) extending survival, but most patients still succumb (Burd et al. Nat Med 2020). Therefore, developing more efficient, less toxic, and immune-based therapies for AML is an urgent unmet need. Previous studies showed that stromal cell-derived IL-33 stimulates myeloproliferative neoplasms (Mager et al. J Clin Invest 2015). Stimulation-2 (ST2), IL-33 receptor, contributes to leukemia stem cells (LSCs) survival in Cbfb-MYH11 mice (Wang et al . Sci Rep 2019). We showed that ST2 blockade enhanced graft versus leukemia activity against MLL-AF9 egfp AML after hematopoietic cell transplantation (Zhang et al . Sci Transl Med 2015). We and others, also, found that ST2 is expressed on normal murine and human hematopoietic stem cells (HSCs), respectively (Capitano et al. Blood Cells Mol Dis 2020; Alt et al. Biol Blood Marrow Transplant 2019). These data suggest a leukemia-promoting role of ST2/IL-33 signaling. To determine clinical relevance of ST2 in AML, we generated Kaplan-Meier curves using TCGA (n=173) and TARGET AML (n=187) databases. Decreased survival was observed in patients with high IL1RL1 (ST2 gene) which was validated in an independent database (AMLCG 1999 trial, n=417) (Fig. 1A). Since ST2 is expressed on HSCs, we interrogated if ST2 is expressed on LSCs defined as CD34 +CD38 - in the Princess Margaret Leukemia biobank (n=192), and found ST2 is higher on LSCs vs CD34 -CD38 +/- cells (Fig. 1B). We then sought to analyze ST2 on bone marrow samples comparing complete responders vs refractory patients to note that ST2 expression was increased in refractory patients' LSCs (Fig. 1C). To scrutinize the role of ST2 in initiating leukemogenesis, we performed limiting dilution transplantation using 500, 200, and 50 Lin -Sca-1 +c-KIT +-sorted LSCs from WT vs ST2 -/- MLL-AF9 egfp transduced cells. Frequency of LSCs in ST2 -/- cells was decreased by ~15-fold as opposed to WT cells [1:2141 (1:546-1:8405) vs 1:145 (1:75-1:283), p=3.37e-05] (Fig. 2A). We also tested leukemia maintenance, secondary transplantations from the primary recipients resulted in leukemia growth delay in ST2 -/- vs WT cells which was confirmed in tertiary transplantations (Fig. 2B-E). Self-renewal ability of LSCs is correlated to reactive oxygen species (ROS) (Testa et al. Exp Hematol 2016), and we found that ROS levels in ST2 -/- leukemic cells are markedly diminished in contrast to WT leukemic cells (Fig. 2F). ST2 deficiency in leukemic cells arrests G2/S/M cell cycle progression in LSCs (Fig. 2G-J). These data indicated that ST2 is indispensable for initiating and maintaining LSCs in MLL-AF9 AML. We next developed murine and human Fc-silenced-bispecific antibodies engaging mouse or human ST2 and CD3 (BsAb) built on the IgG[L]-scFv platform with proven ability to drive T cells into human tumors for effective tumor ablation (Santich et al. Sci Transl Med 2020; Park et al. J Immunother Cancer 2021) (Fig. 3A, 3E). Both BsAbs showed >90% purity by HPLC, stability under heat stress and low endotoxin. Animals did not exhibit any in vivo toxicity at BsAb doses of 0.4, 2, 5, 10 μg ip q 3 days x 6 doses (not shown). In the immunocompetent MLL-AF9 mice, murine anti-ST2 BsAb (BC281) treatment (10 μg i.p, 4 days post-AML challenge and given every three days for a total of 6 injections) resulted in extended survival compared to isotype control mice (Fig. 3B). Leukemic cells and LSCs were accordingly decreased in treated vs control group (Fig. 3C-D). We modeled humanized leukemic mice with MOLM-14 egfp cells and weekly injection of human CD8 + T cells in NOD.Cg-Prkdc scid Il2rg tm1Wjl/SzJ (NSG) mice (Fig. 3F). Animals treated with human anti-ST2 BsAb (BC282), using a similar regimen as for the immunocompetent model, led to better survival when compared to animals treated with mutated non-functional anti-ST2 BsAb (BC283) (Fig. 3G). Frequency of MOLM-14 egfp cells was lower in the BC282 vs BC283 group (Fig. 3H). These results suggested that anti-ST2 BsAbs can inhibit AML growth to improve survival. We concluded that ST2 is a potential therapeutic target, and ST2-specific T cell engaging BsAbs represent promising immunotherapeutics for AML. Figure 1 Figure 1. Disclosures Cheung: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application; Y-mabs Therapeutics and Abpro-Labs Inc: Patents & Royalties: inventor on multiple patents filed by MSK, including those licensed to Ymabs Therapeutics, Biotec Pharmacon, and Abpro-labs; Eureka Therapeutics: Membership on an entity's Board of Directors or advisory committees. Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application.
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Brint, Elizabeth K., Katherine A. Fitzgerald, Philip Smith, Anthony J. Coyle, Jose-Carlos Gutierrez-Ramos, Padraic G. Fallon, and Luke A. J. O'Neill. "Characterization of Signaling Pathways Activated by the Interleukin 1 (IL-1) Receptor Homologue T1/ST2." Journal of Biological Chemistry 277, no. 51 (October 3, 2002): 49205–11. http://dx.doi.org/10.1074/jbc.m209685200.
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T1/ST2 is a member of the interleukin (IL)-1 receptor superfamily, possessing three immunoglobulin domains extracellularly and a Toll/IL1R (TIR) domain intracellularly. The ligand for T1/ST2 is not known. T1/ST2 is expressed on Type 2 T helper (Th2) cells, and its role appears to be in the regulation of Th2 cell function. Here, we have investigated T1/ST2 signal transduction, using either transient overexpression of T1/ST2 or a cross-linking monoclonal antibody to activate cells. We demonstrate that T1/ST2 does not activate the transcription factor NF-κB when overexpressed in murine thymoma EL4 cells, or in the mast cell line P815 treated with the anti-T1/ST2 antibody. However, a chimera comprising the extracellular domain of the type 1 IL-1 receptor and the intracellular domain of T1/ST2 activates NF-κB both by overexpression and in response to IL-1. This artificial activation requires the IL1RAcP recruited via the extracellular portion (IL1R1) of the chimera. T1/ST2 is, however, able to activate the transcription factor activator protein-1 (AP-1), increase phosphorylation of c-Jun, and activate the MAP kinases c-Jun N-terminal kinase (JNK), p42/p44 and p38. Anti-T1/ST2 also induces the selective expression of IL-4 but not IFN-γ in naive T cells. Importantly, this effect is blocked by prior treatment with the JNK inhibitor SP600125 confirming that JNK as a key effector in T1/ST2 signaling. The lack of effect on NF-κB when T1/ST2 is homodimerized identifies T1/ST2 as the first member of the IL-1 receptor superfamily so far studied that is apparently unable to activate NF-κB, consistent with evidence indicating the lack of a role for NF-κB in Th2 cell function.
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Alvarez, Fernando, Jorg H. Fritz, and Ciriaco A. Piccirillo. "IL-1 and IL-33 differentially regulate the functional specialization of mucosal Foxp3+ regulatory T cells." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 116.20. http://dx.doi.org/10.4049/jimmunol.200.supp.116.20.
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Abstract CD4+ regulatory T (TREG) cells are critical mediators of peripheral immune tolerance and homeostasis, and express the forkhead box p3 (Foxp3) transcription factor, the master-regulator driving the programming of the TREG cell suppressive phenotype. TREG cells are abundant at mucosal surfaces, where they acquire tissue-specific adaptations. The biological consequences of these adaptations on the stability of thymic-derived TREG (tTreg) cells remain largely unknown. To determine the signals that drive the fate of TREG cells, we isolated and compared stable from unstable TREG cells using a TREG transfer model where we previously observed the functional reprogramming of Foxp3+ TREG cells into Th1/Th17 effector T cells. We identified the expression of the IL-33 receptor (IL-33R, ST2) on stable tTREG cells and the IL-1 receptor (IL1R1) on unstable exTREG cells undergoing functional reprogramming. We show that both TREG cell populations represent competing subsets in inflammatory conditions. This is further underlined by the fact that the absence of IL1R1 expression (IL1R1−/−) leads to the accumulation of ST2+ TREG cells at mucosal sites in vivo. In two distinct lung infection models, we demonstrate that ST2-expressing TREG cells express GATA3 and resist production of inflammatory cytokines, whereas IL1R1-expressing TREG cells express RORγT and lose Foxp3 expression in vivo. While IL-1 signaling impairs TREG cell suppressive function, ST2 is required for the maintenance of the lineage identity and suppressive function of TREG cells. These observations demonstrate that IL-1 and IL-33 produced during immune challenge exert distinct roles on the functional adaptation of Foxp3+ tTREG cells at mucosal surfaces.
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Chou, Hsin-Hua, Lung-An Hsu, Jyh-Ming Jimmy Juang, Fu-Tien Chiang, Ming-Sheng Teng, Semon Wu, and Yu-Lin Ko. "Synergistic Effects of Weighted Genetic Risk Scores and Resistin and sST2 Levels on the Prognostication of Long-Term Outcomes in Patients with Coronary Artery Disease." International Journal of Molecular Sciences 23, no. 8 (April 13, 2022): 4292. http://dx.doi.org/10.3390/ijms23084292.
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Resistin and soluble suppression of tumorigenicity 2 (sST2) are useful predictors in patients with coronary artery disease (CAD). Their serum levels are significantly attributed to variations in RETN and IL1RL1 loci. We investigated candidate variants in the RETN locus for resistin levels and those in the IL1RL1 locus for sST2 levels and evaluated the prognostication of these two biomarkers and the corresponding variants for long-term outcomes in the patients with CAD. We included 4652, 557, and 512 Chinese participants from the Taiwan Biobank (TWB), cardiovascular health examination (CH), and CAD cohorts, respectively. Candidate variants in RETN and IL1RL1 were investigated using whole-genome sequence (WGS) and genome-wide association study (GWAS) data in the TWB cohort. The weighted genetic risk scores (WGRS) of RETN and IL1RL1 with resistin and sST2 levels were calculated. Kaplan–Meier curves were used to analyze the prognostication of resistin and sST2 levels, WGRS of RETN and IL1RL1, and their combinations. Three RETN variants (rs3219175, rs370006313, and rs3745368) and two IL1RL1 variants (rs10183388 and rs4142132) were independently associated with resistin and sST2 levels as per the WGS and GWAS data in the TWB cohort and were further validated in the CH and CAD cohorts. In combination, these variants explained 53.7% and 28.0% of the variation in resistin and sST2 levels, respectively. In the CAD cohort, higher resistin and sST2 levels predicted higher rates of all-cause mortality and major adverse cardiac events (MACEs) during long-term follow-up, but WGRS of RETN and IL1RL1 variants had no impact on these outcomes. A synergistic effect of certain combinations of biomarkers with RETN and IL1RL1 variants was found on the prognostication of long-term outcomes: Patients with high resistin levels/low RETN WGRS and those with high sST2 levels/low IL1RL1 WGRS had significantly higher all-cause mortality and MACEs rates, and those with both these combinations had the poorest outcomes. Both higher resistin and sST2 levels, but not RETN and IL1RL1 variants, predict poor long-term outcomes in patients with CAD. Furthermore, combining resistin and sST2 levels with the WGRS of RETN and IL1RL1 genotyping exerts a synergistic effect on the prognostication of CAD outcomes. Future studies including a large sample size of participants with different ethnic populations are needed to verify this finding.
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Hansen, Nils, Kristian Reckzeh, Helena Agerstam, Maria Askmyr, Sandra Gordon, Marianne Rissler, Carl Högberg, Johan Richter, Marcus Järås, and Thoas Fioretos. "Upregulation Of IL1RAP On Human Progenitor/Stem Cells Induces Features Of a Myeloproliferative Disorder In Mice." Blood 122, no. 21 (November 15, 2013): 1650. http://dx.doi.org/10.1182/blood.v122.21.1650.1650.
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Abstract Myeloid malignancies, including chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML), display upregulation of IL1RAP at the cell surface of the primitive (CD34+CD38-) leukemic cells (Järås et al. PNAS, 2010; Barreyro et al. Blood, 2012; Askmyr et al. Blood 2013). IL1RAP is an essential co-receptor for the interleukin-1 (IL1R1) and the interleukin-33-receptors (IL33R, ST2) to convey signals upon binding by their ligands IL1 and IL33, respectively. IL1RAP has previously mainly been studied in the context of inflammation and little is known about its role in normal hematopoiesis and if it’s upregulation in malignant hematopoiesis is of pathogenetic importance. In this study, we first characterized normal hematopoiesis in Il1rap(-/- ) mice, and discovered that these mice displayed a reduction in myeloid cells in the peripheral blood (9.8x10^5 vs. 1.68x10^6 myeloid cells per mL, p=0.0076), suggesting that Il1rap is involved myelopoiesis. To test whether Il1rap regulates normal hematopoietic stem cells (HSC), we performed competitive stem cell transplantations, and demonstrated that Il1rap-/- HSC gave rise to equal donor contribution as Il1rap+/+ HSC, even in secondary transplantations, suggesting that Il1rap is dispensable for normal HSC function. As IL1RAP is upregulated in myeloid neoplasms but it has been unclear whether this upregulation is functionally involved in disease biology, we next explored if IL1RAP upregulation alone is sufficient to cause features of a myeloid neoplasm. To this end, we retrovirally expressed IL1RAP along with GFP in cord blood (CB) CD34+ cells and transplanted the cells to NSG mice. At 200 days post transplantation, a striking myeloid lineage skewing (67% N=6, vs. 34% N=3, CD33+ among GFP+ cells in bone marrow, p=0.031), accompanied by a reduction of CD19+ cells (21% vs. 53%, p=0.041), was observed in mice that had received IL1RAP overexpressing (IL1RAP+) cells. In addition, mice that had received IL1RAP+ cells displayed enlarged spleens (102 mg vs. 71mg, p=0.034) and showed a myeloid cell expansion when compared to MIG control mice (10% vs. 3.7% CD33+ among GFP+ cells, p=0.035). Having demonstrated that IL1RAP is involved in steady-state myelopoiesis and that IL1RAP upregulation leads to myeloid lineage skewing, we next investigated if primary CML primitive cells display a different sensitivity for cytokines (IL1B and IL33) that signal through IL1RAP-associated receptors. CB and CML cells were stimulated with either single cytokines or cytokines in combination with SCF, in serum free liquid cultures. Whereas IL1B did not affect the in vitro proliferation of normal CB CD34+ cells, primary CML CD34+ cells, and particularly CML CD34+CD38- cells, showed a strong response to IL1B stimulation with more than 10-fold higher cell counts compared to unstimulated CML CD34+CD38- cells, following 7 days of culture (5.6x103 vs. 7.5x104 cells p= 0.006), while IL33 had minor effects (5.6x103 vs. 8.5x103 p=0.040), suggesting that IL1RAP upregulation may render primitive malignant myeloid cells hypersensitive to IL1B stimulation. In summary, these findings demonstrate that IL1RAP is involved in steady state myelopoiesis and that enforced IL1RAP expression, in cord blood CD34+ cells, alone is sufficient to induce features of a myeloproliferative disorder in mice. Primitive CML cells with upregulation of IL1RAP at the cell surface were more sensitive to IL1B compared to corresponding normal cells, which were unaffected. Collectively, these observations suggest that IL1RAP upregulation may contribute to the pathogenesis of myeloid neoplasms. Disclosures: Richter: Cantargia: Consultancy, Equity Ownership. Järås:Cantargia: Equity Ownership. Fioretos:Cantargia AB: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding.
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Kubota, Yasushi, Ivo Lieberam, Shinya Kimura, Thomas M. Jessell, and Shin-Ichi Nishikawa. "Plxdc2 Marks Hematopoietic Stem Cells and Th2 Cytokine-Producing Innate Lymphocytes in Adult Bone Marrow." Blood 118, no. 21 (November 18, 2011): 1278. http://dx.doi.org/10.1182/blood.v118.21.1278.1278.
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Abstract Abstract 1278 Hematopoietic stem cells (HSCs) have been highly enriched using combinations of more than 10 surface markers. However the simple method using a few positive markers is preferable to identify HSCs location in tissue section. We performed a stringent comparative gene expression profiling analysis to find genes preferentially expressed in the HSC population, and identified a total of 63 genes that are highly expressed in HSC among various hematopoietic cell population. In order to find HSC-specific marker we focused on genes encoding cell surface protein, and found that plexin domain containing 2 (Plxdc2) is highly expressed in CD34—c-Kit+Sca-1+Lineage−(CD34−KSL) HSC population using Plxdc2::GFP knock-in mice. Only 0.2% of whole bone marrow cells were Plxdc2+, and competitive repopulation assay clearly showed that all HSCs are included in the Plxdc2+ fraction. These results identify Plxdc2 as a new marker of HSCs. Plxdc2+ population contain not only HSCs but uncharacterized c-Kitlow/−Sca-1+Lineage−cells. To further purify HSCs, we investigated the additional positive marker. Throughout the screening of various known HSC-related marker, CD150 was selected. CD150 is already recognized as a positive HSC marker (Kiel, et al. Cell 2005). The Plxdc2+CD150+ fraction represented only 0.1%±0.002% in whole bone marrow, and 6% in c-Kit+Sca-1+Lineage− cells, respectively. To test whether the combination of Plxdc2 and CD150 with or without other markers can highly enrich long-term HSCs, we competitively reconstituted irradiated mice with single Plxdc2+CD150+ cells or single Plxdc2+CD150+c-Kit+Sca-1+Lineage− cells. One out of every 4.6 Plxdc2+CD150+ cells (22%), and one out of 2.2 Plxdc2+CD150+c-Kit+Sca-1+Lineage− cells (44%) engrafted and gave long-term multi-lineage reconstitution. The simple combination of Plxdc2 and CD150 significantly increased HSC purity. In addition, we found robust levels of PLXDC2 transcripts in purified human cord blood CD34+ HSCs. Next, we attempted to characterize the another Plxdc2+ fraction which is c-Kitlow/−Sca-1+Lineage−. Multicolor flowcytometric analysis revealed that Plxdc2+c-Kitlow/−Sca-1+Lineage− cells uniformly express CD45, IL7Rα, Thy-1.2, CD27, T1/ST2 (IL1RL1, a subunit of IL33R) and CD25. These cell surface phenotype indicated that this population is probably of lymphoid lineage. However, culturing Plxdc2+ c-Kit low/−Sca-1+Lineage− cells on OP9-DL1, which supports the development of T-cell progenitors to mature T-cells, did not induce T-cell differentiation. Plxdc2+c-Kitlow/−Sca-1+Lineage−cells also did not differentiate into B cells when co-cultured with OP9 stroma cell line. Furthermore Plxdc2+c-Kitlow/−Sca-1+Lineage− cells produce IL-5 and IL-13 in response to IL-33 or a combination of IL-2 and IL-25. These characteristics resemble that of “natural helper (NH) cells”, a recently identified cell population capable of producing large amounts of Th2 cytokines in fat-associated lymphoid clusters (Moro, et al. Nature 2010). Immunohistochemical staining of bone section to detect HSCs, and functional analyses to clarify why Plxdc2 specifically express in HSCs and bone marrow “NH cells” using Plxdc2-deficient mice are our ongoing tasks. Disclosures: No relevant conflicts of interest to declare.
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Tkachev, Victor, Scott N. Furlan, E. Lake Potter, Hengqi Zheng, Daniel J. Hunt, Lucrezia Colonna, Agne Taraseviciute, et al. "Uncovering the Molecular Signature of Pathogenic Tissue-Infiltrating T Cells during Acute Graft-Versus-Host Disease." Blood 132, Supplement 1 (November 29, 2018): 805. http://dx.doi.org/10.1182/blood-2018-99-113652.
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Abstract One of the major barriers to developing targeted therapies for aGVHD control is the difficulty in identifying T cell signatures specific for GVHD pathology while distinguishing these from the pathways essential for tissue-specific T cell immune reconstitution. To address this need we have interrogated the migration patterns, as well as the phenotypic and transcriptomic characteristics of allogeneic T cells infiltrating aGVHD target organs in non-human primates. To rigorously study T cell migration during aGVHD we tracked T cells labeled following in vivo infusion with fluorescently tagged anti-CD45 antibodies given to NHP transplant recipients with aGVHD on day 8 post-HCT, during active disease. Anti-CD45 antibodies with distinct fluorescent tags were given at 6 hours before necropsy (anti-CD45-AlexaFluor647) and 5 minutes before necropsy (anti-CD45-AlexaFluor488), in order to measure T cells that were in the circulation and those migrating to GVHD target tissues, based on their labeling with one or both fluorescently-tagged antibodies. These experiments identified increased migration of both allogeneic CD8 T cells (Figure 1A) and CD4 T cells (not shown) during aGVHD, with trafficking into secondary lymphoid organs as well as non-lymphoid GVHD target organs (intestine and kidney). While migration was increased during aGVHD, these T cells, which demonstrated some phenotypic similarities to CD8 T cells in the peripheral blood (Figure 1B), also adopted tissue-specific phenotypes as measured by flow cytometry (Figure 1C), including the expression of canonical markers of resident-memory T cells (CD69+CD103-/+). However, unlike the tissue-resident T cells in healthy controls during homeostasis, tissue-infiltrating T cells during aGVHD expressed multiple markers of activation, including Ki67 and Granzyme B (Figure 1D). These flow cytometric characteristics suggested that the phenotype of organ-infiltrating T cells during aGVHD included attributes of both tissue-residency and of pathogenic alloreactivity. To further identify aGVHD-specific signatures, we performed transcriptomic analysis of tissue-infiltrating T cells during aGVHD. Using an unsupervised weighted gene correlation network analysis (WGCNA) we characterized the gene sets associated with individual GVHD target organs (Figure 2). We found that tissue-infiltrating T cells during aGVHD could be characterized by divergent features: First, they maintained a core tissue localization signature, which included genes previously linked to tissue-resident T cells (e.g. RUNX3, IFNG, CXCR6). Importantly, however, they also acquired an aGVHD-specific transcriptional signature including expression of IL1RL1 (encoding ST2), ICOS, TNFRSF9 (CD137) and TNFRSF4 (OX40). This signature also included enrichment for transcripts encoding the cytotoxic mediators GRMB and GRMA, the proliferation markers MKI67 and AURKA, as well as cytokines and cytokine receptors (IL18, IL18R, IL21, IL21R). Proteins encoded by each of these transcripts have been linked to aGVHD-causing T cells, strengthening the inference that these constitute a robust transcriptomic signature of aGVHD pathogenesis. Thus, for the first time in a large-animal model, we have been able to directly measure both the kinetics and the protein and RNA expression signatures of T cells during their migration into aGVHD target organs, This study provides new evidence for the evolution of a phenotypic and transcriptomic dichotomy during aGVHD-mediated tissue infiltration, in which T cells take on both tissue- and aGVHD-specific characteristics. These data provide novel insights into the spatial organization of systemic alloimmunity during aGVHD, which should enable more precise targeting of pathogenic T cell populations while preserving normal tissue immune reconstitution after transplantation. Disclosures Tkachev: Regeneron Pharmaceuticals, Inc.: Research Funding. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Kean:Regeneron Pharmaceuticals, Inc.: Research Funding.
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Lin, Jeng-Feng, Semon Wu, Jyh-Ming Jimmy Juang, Fu-Tien Chiang, Lung-An Hsu, Ming-Sheng Teng, Shih-Tsung Cheng, et al. "IL1RL1 single nucleotide polymorphism predicts sST2 level and mortality in coronary and peripheral artery disease." Atherosclerosis 257 (February 2017): 71–77. http://dx.doi.org/10.1016/j.atherosclerosis.2016.12.020.
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Wang, X., Y. F. Zhu, D. M. Li, Q. Qin, Q. Wang, F. S. Muhali, W. J. Jiang, and J. A. Zhang. "Polymorphisms of ST2-IL18R1-IL18RAP gene cluster: a new risk for autoimmune thyroid diseases." International Journal of Immunogenetics 43, no. 1 (November 14, 2015): 18–24. http://dx.doi.org/10.1111/iji.12240.
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Barreyro, Laura, Britta Will, Boris Bartholdy, Li Zhou, Tihomira I. Todorova, Robert Stanley, Susana Ben-Neriah, et al. "Parallel Transcriptional Analysis of Multiple Stem and Progenitor Populations Identifies Novel Commonly Dysregulated and Functionally Relevant Targets in AML." Blood 120, no. 21 (November 16, 2012): 1875. http://dx.doi.org/10.1182/blood.v120.21.1875.1875.
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Abstract Abstract 1875 Recent experimental evidence suggests that acute myeloid leukemia (AML) originates from hematopoietic stem and progenitor cells (HSPC) following the acquisition of multiple genetic or epigenetic changes that initially give rise to pre-leukemic HSPC (pre-LSC) and then to fully transformed leukemia stem cells (LSC). Relapse continues to be the major cause of death in most subtypes of AML, suggesting that current therapies are largely ineffective in eliminating LSC and pre-LSC. Cellular heterogeneity and the recent observation that LSC are contained within different phenotypic cellular compartments are challenges for the identification of pathways contributing to the initiation and maintenance of AML. To address these challenges we employed a novel strategy of parallel transcriptional analysis of multiple phenotypic HSPC populations from individuals with AML with normal karyotype (N=5), -7/7q- (N=6) and complex karyotype (N=5), including long-term HSC, short-term HSC, and granulocyte-monocyte progenitors (GMP), and comparison to corresponding cell populations from age-matched healthy controls (HC) (N=6). Specifically, we sorted Lin−/CD34+/CD38−/CD90+ (LT-HSC), Lin−/CD34+/CD38−/CD90− (ST-HSC), and Lin−/CD34+/CD38+/CD123+/CD45RA+ (GMP), and hybridized RNA to Affymetrix GeneST 1.0 expression arrays. Differential gene expression was determined within each compartment by direct comparison of AML LT-HSC vs. HC LT-HSC, AML ST-HSC vs. HC ST-HSC, and AML GMP vs. HC GMP. Subsequent intersection of all differentially expressed genes revealed that only a relatively small number of 6 to 11 genes were consistently dysregulated in all examined leukemic stem and progenitor cell compartments. Interleukin 1 receptor accessory protein (IL1RAP) was one of the most significantly upregulated genes in LT-HSC, ST-HSC, and GMP in all examined subtypes of AML. IL1RAP is a transmembrane protein required for signaling through several receptors of the IL1 family, including IL-1R1 and ST2. We detected significant overexpression of IL1RAP protein on HSC and progenitor cells of AML patients. Interestingly, CD34+/Lin+ precursor cells showed only a marginal increase of IL1RAP at the protein level in AML, underscoring the importance of purifying HSPC with stringent lineage depletion. We performed fluorescence in situ hybridization in sorted IL1RAP+ and IL1RAP− cells from -7 AML. We observed that the -7 clone was restricted to IL1RAP+ cells, while IL1RAP- cells did not display monosomy 7, demonstrating that IL1RAP overexpression is a distinguishing feature of the cells of the -7 clone. Patients with normal karyotype AML showed a wider range of IL1RAP expression levels; some were as high as in -7 AML and others were as low as in HC. We asked whether IL1RAP expression levels were associated with known clinical or molecular parameters. We analyzed two published datasets of patients with normal karyotype AML (Metzeler, Blood. 2008;112:4193–4201; Tomasson, Blood. 2008;111:4797–4808). Patients with high IL1RAP levels showed inferior overall survival than patients with lower IL1RAP (p=2.2×10−7; median survival: 7.82 mo. for IL1RAP high, 20 mo. for IL1RAP low). Multivariate analysis using a Cox regression model showed that high IL1RAP status was an independent prognostic factor (p=0.002), and even stronger than FLT3 mutation status (p=0.006). In addition, we analyzed data from 183 patients with MDS and found IL1RAP expression to be specifically elevated in cases with RAEB-2, suggesting a role of IL1RAP in MDS and in the progression to AML. Downregulation of IL1RAP protein expression in 4 AML cell lines (THP1, OCI-AML3, HL60, HEL) led to a significant 45–98% decrease in clonogenic growth and increased apoptosis in vitro. To assess the effects of IL1RAP downregulation in vivo, we performed xenotransplants into immunodeficient NOD/SCID/IL2Rg-null mice. THP-1 AML cells showed a 92% reduced proliferation and infiltration of hematopoietic organs upon IL1RAP knockdown in comparison to a non-silencing control in vivo. Genetic studies to assess the role of IL1RAP in the initiation and maintenance of AML in an IL1RAP−/− mouse model are currently ongoing. In summary, our study provides a map of consistently dysregulated transcripts across multiple fractionated stem and progenitor cell types from patients with AML, and identifies IL1RAP as a putative new therapeutic and prognostic target in stem cells in AML and MDS. Disclosures: No relevant conflicts of interest to declare.
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Worrall, Bradford B., Thomas G. Brott, Robert D. Brown, W. Mark Brown, Stephen S. Rich, Sampath Arepalli, Fabienne Wavrant-De Vrièze, et al. "IL1RN VNTR Polymorphism in Ischemic Stroke." Stroke 38, no. 4 (April 2007): 1189–96. http://dx.doi.org/10.1161/01.str.0000260099.42744.b0.
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Qian, Zuanhao, Zhenglei Zhang, and Yingying Wang. "T cell receptor signaling pathway and cytokine-cytokine receptor interaction affect the rehabilitation process after respiratory syncytial virus infection." PeerJ 7 (June 12, 2019): e7089. http://dx.doi.org/10.7717/peerj.7089.
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Background Respiratory syncytial virus (RSV) is the main cause of respiratory tract infection, which seriously threatens the health and life of children. This study is conducted to reveal the rehabilitation mechanisms of RSV infection. Methods E-MTAB-5195 dataset was downloaded from EBI ArrayExpress database, including 39 acute phase samples in the acute phase of infection and 21 samples in the recovery period. Using the limma package, differentially expressed RNAs (DE-RNAs) were analyzed. The significant modules were identified using WGCNA package, and the mRNAs in them were conducted with enrichment analysis using DAVID tool. Afterwards, co-expression network for the RNAs involved in the significant modules was built by Cytoscape software. Additionally, RSV-correlated pathways were searched from Comparative Toxicogenomics Database, and then the pathway network was constructed. Results There were 2,489 DE-RNAs between the two groups, including 2,386 DE-mRNAs and 103 DE-lncRNAs. The RNAs in the black, salmon, blue, tan and turquoise modules correlated with stage were taken as RNA set1. Meanwhile, the RNAs in brown, blue, magenta and pink modules related to disease severity were defined as RNA set2. In the pathway networks, CD40LG and RASGRP1 co-expressed with LINC00891/LINC00526/LINC01215 were involved in the T cell receptor signaling pathway, and IL1B, IL1R2, IL18, and IL18R1 co-expressed with BAIAP2-AS1/CRNDE/LINC01503/SMIM25 were implicated in cytokine-cytokine receptor interaction. Conclusion LINC00891/LINC00526/LINC01215 co-expressed with CD40LG and RASGRP1 might affect the rehabilitation process of RSV infection through the T cell receptor signaling pathway. Besides, BAIAP2-AS1/CRNDE/LINC01503/SMIM25 co-expressed with IL1 and IL18 families might function in the clearance process after RSV infection via cytokine-cytokine receptor interaction.
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HogenEsch, Harm, Srikanth Elesela, Syu-Jhe Chien, Kathleen Silva, Vicki Kennedy, and John P. Sundberg. "Role of group 2 innate lymphoid cells (ILC2) in SHARPIN-deficient mice." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 221.15. http://dx.doi.org/10.4049/jimmunol.198.supp.221.15.
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Abstract SHARPIN is a component of the linear ubiquitination assembly complex and a key regulator of NFkB and integrin signaling. SHARPIN-deficient mice develop a phenotype known as chronic proliferative dermatitis (cpdm), characterized by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. We recently reported that the cutaneous inflammation in SHARPIN-deficient mice (Sharpincpdm) develops independently of B and T lymphocytes. We therefore sought to determine the role of innate lymphoid cells (ILCs) in the dermatitis of Sharpincpdm mice. ILCs were identified as a discrete population of CD45+ Lin−CD90.2hi cells in the skin and draining lymph nodes (LN) of wild type (WT) and Sharpincpdm mice. The number of ILCs was markedly increased in Sharpincpdm mice. The majority of cells were group 2 ILC (ILC2) as indicated by labeling for GATA3, IL5, and IL13. The skin of Sharpincpdm mice had increased expression of Il33 and Tslp mRNA. To determine the role of IL33, double mutant mice were generated in which the receptor for IL33 (Il1lr1 also known as ST2) was deleted. Loss of IL33-signaling greatly reduced the number of ILCs and reduced the severity of the dermatitis. These experiments suggest that the dermatitis in Sharpincpdm mice is driven by IL33-dependent ILC2. Supported by the NIH (AR049288).
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Mizoguchi, Yoko, Miyuki Tsumura, Satoshi Okada, Hidemasa Sakai, Ryuta Nishikomori, Shin'ichiro Yasunaga, Motoaki Ohtsubo, et al. "A Novel Mutation K673R In STAT1 Impaired the STAT1 Signal Transduction In a dominant– Negative Manner Identified In a Japanese Boy with MSMD." Blood 116, no. 21 (November 19, 2010): 1734. http://dx.doi.org/10.1182/blood.v116.21.1734.1734.
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Abstract Abstract 1734 Mendelian susceptibility to mycobacterial disease (MSMD) is a rare congenital disorder characterized by susceptibility to infection by poorly virulent intracellular pathogens such as BCG, non-tuberculosis mycobacterium and Salmonellae. MSMD is associated with genetic defects in the IL-12/IFN-γ pathway, and six responsible genes, IFNGR1, IFNGR2, IL12B, IL12RB1, STAT1, and NEMO have been identified so far. Singnal transducer and activation of transcription 1 (STAT1) is a DNA-binding factor which regulates specific gene transcription. IFN-γ stimulation results in phosphorylation of STAT1 at Tyr701 (Y701) to induce the homodimerization, so called a gamma-activated factor (GAF), through the conformational change and the nuclear import. The GAF binds to the gamma-activated sequence (GAS) to induce the transcriptional activities. Patients with STAT1 deficiency were known in both recessive and dominant forms and three mutations in STAT1, L706S, E320Q and Q463H, have previously been reported from three family with an autosomal-dominant form of STAT1 partial deficiency. L706S mutation in the tail segment domain of STAT1 is shown to impair the phosphorylation at Tyr701. Although the phosphorylation is normal in other two mutations, the E320Q or Q463H mutant, in which the DNA-binding ability was abolished. Here we identified a novel heterozygous STAT1 mutation, 2018A>G (K673R), in a Japanese patient with MSMD. This was thought to be first report whose mutation was identified in the SH2 domain of autosomal-dominant form of STAT1. He had a past history of BCGitis after vacctination and multifocal osteomyelitis at the age of 5. Bone biopsy revealed granulomatous change without detecting Mycobacterium. The same mutation was also identified in his father and older sister. Although his sister had a history of BCGitis, his father had no clinical manifestations. A peripheral blood mononuclear cells from the patient could not sufficiently produce TNF-α in response to IFN-γ. EB-transformed B cells from the patient showed that induction of STAT1 phosphorylation by IFN-γ was partially impaired. We generated Flag-tagged STAT1 expression constructs of wild-type (WT) and three mutants including our mutant and analyzed molecular functions along with STAT1 signaling. K673R STAT1 showed partial impairment in the phosphorylation in response to both IFN-α and IFN-γ. Further, the electrophoretic mobility shift assay revealed that the K673R mutant abolished the DNA-binding ability. The nuclear translocation was normally detected. Curiously, dose-dependent negative effect on WT STAT1 was observed in K673R mutant by the reporter assay. K673R mutant interacted with WT to abrogate the DNA-binding activity, thus, exerted a dominant-negative effect on the transcription activity of WT STAT1. Based on these results, a novel heterozygous mutation, K673R, in SH2 domain of the STAT1 gene impaired the STAT1 signal transduction in a dominant-negative manner. K673R mutation in STAT1 may play an important role in molecular pathogenesis of MSMD. Disclosures: No relevant conflicts of interest to declare.
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Schaunaman, Niccolette, Amelia Sanchez, Kris Genelyn Dimasuay, Nicole Pavelka, Mari Numata, Rafeul Alam, Richard J. Martin, and Hong Wei Chu. "Interleukin 1 Receptor-Like 1 (IL1RL1) Promotes Airway Bacterial and Viral Infection and Inflammation." Infection and Immunity 87, no. 7 (May 6, 2019). http://dx.doi.org/10.1128/iai.00340-19.
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ABSTRACT Interleukin 1 receptor-like 1 (IL1RL1), also known as suppression of tumorigenicity 2 (ST2), is the receptor for interleukin 33 (IL-33) and has been increasingly studied in type 2 inflammation. An increase in airway IL-33/ST2 signaling in asthma has been associated with eosinophilic inflammation, but little is known about the role of ST2 in neutrophilic inflammation. Airway Mycoplasma pneumoniae and human rhinovirus (HRV) infections are linked to neutrophilic inflammation during acute exacerbations of asthma. However, whether ST2 contributes to M. pneumoniae- and HRV-mediated airway inflammation is poorly understood. The current study sought to determine the functions of ST2 during airway M. pneumoniae or HRV infection. In cultured normal human primary airway epithelial cells, ST2 overexpression (OE) increased the production of neutrophilic chemoattractant IL-8 in the absence or presence of M. pneumoniae or HRV1B infection. ST2 OE also enhanced HRV1B-induced IP-10, a chemokine involved in asthma exacerbations. In the M. pneumoniae-infected mouse model, ST2 deficiency, in contrast to sufficiency, significantly reduced the levels of neutrophils following acute (≤24 h) infection, while in the HRV1B-infected mouse model, ST2 deficiency significantly reduced the levels of proinflammatory cytokines KC, IP-10, and IL-33 in bronchoalveolar lavage (BAL) fluid. Overall, ST2 overexpression in human epithelial cells and ST2 sufficiency in mice increased the M. pneumoniae and HRV loads in cell supernatants and BAL fluid. After pathogen infection, ST2-deficient mice showed a higher level of the host defense protein lactotransferrin in BAL fluid. Our data suggest that ST2 promotes proinflammatory responses (e.g., neutrophils) to airway bacterial and viral infection and that blocking ST2 signaling may broadly attenuate airway infection and inflammation.
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Liu, Renli, Liping Liu, Chaojie Wei, and Dong Li. "IL-33/ST2 immunobiology in coronary artery disease: A systematic review and meta-analysis." Frontiers in Cardiovascular Medicine 9 (October 20, 2022). http://dx.doi.org/10.3389/fcvm.2022.990007.
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The IL-33/ST2 axis is reported to be controversially associated with coronary artery disease (CAD). A systematic review of the association between the IL-33/ST2 axis and CAD revealed that IL-33/ST2 plays a protective role in CAD and serum sST2 and IL-33 levels are increased in patients with cardiovascular disease. Therefore, the association of IL-33/ST2 single nucleotide polymorphisms (SNPs) with CAD prevalence, prognosis, and risk factors was assessed by performing a meta-analysis. Through a literature search of relevant articles in various databases using the relevant keywords, seven studies were included in the analysis. The meta-analysis showed that the IL-33/ST2 axis was associated with increased CAD risk [pooled odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.13–1.20]. Gene subgroup analysis showed a close association of IL1RL1 (OR = 1.25, 95% CI: 1.20–1.30; I2 = 85.9%; p = 0.000) and IL1RAcP (OR = 1.42, 95% CI: 1.26–1.60; I2 = 27.1%; p = 0.203) with increased CAD risk. However, the association for the IL-33 gene was not statistically significant. SNPs rs7044343 (T), rs10435816 (G), rs11792633 (C) in IL-33 gene were associated with a protective effect in CAD. However, rs7025417 (T) in IL-33, rs11685424 (G) in IL1RL1, rs950880 (A) in sST2, and rs4624606 (A) in IL1RAcP were related to increased CAD risk. Overall, polymorphisms in IL-33/ST2 axis components were associated with increased CAD risk. These results may help identify key features of IL-33/ST2 immunobiology in CAD along with potential treatment strategies to lower disease burden.
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"IL-33; IL-1 receptor–like 1 (IL1RL1; ST2)." Science-Business eXchange 4, no. 24 (June 2011): 688. http://dx.doi.org/10.1038/scibx.2011.688.
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"IL-1 receptor–like 1 (IL1RL1; ST2); IL-33 (NF-HEV)." Science-Business eXchange 7, no. 17 (May 2014): 488. http://dx.doi.org/10.1038/scibx.2014.488.
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"IL-33 (NF-HEV); IL-1 receptor–like 1 (IL1RL1; ST2)." Science-Business eXchange 3, no. 17 (April 2010): 516. http://dx.doi.org/10.1038/scibx.2010.516.
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Wang, Li, Jun Tang, Xia Yang, Peter Zanvit, Kairong Cui, Wai Lim Ku, Wenwen Jin, et al. "TGF-β induces ST2 and programs ILC2 development." Nature Communications 11, no. 1 (January 7, 2020). http://dx.doi.org/10.1038/s41467-019-13734-w.
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AbstractThe molecular pathways underlying the development of innate lymphoid cells (ILCs) are mostly unknown. Here we show that TGF-β signaling programs the development of ILC2s from their progenitors. Specifically, the deficiency of TGF-β receptor II in bone marrow progenitors results in inefficient development of ILC2s, but not ILC1s or ILC3s. Mechanistically, TGF-β signaling is required for the generation and maintenance of ILC2 progenitors (ILC2p). In addition, TGF-β upregulates the expression of the IL-33 receptor gene Il1rl1 (encoding IL-1 receptor-like 1, also known as ST2) in ILC2p and common helper-like innate lymphoid progenitors (CHILP), at least partially through the MEK-dependent pathway. These findings identify a function of TGF-β in the development of ILC2s from their progenitors.
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Ding, Zhaoyun, Ting Cai, Jupei Tang, Hanxiao Sun, Xinyi Qi, Yunpeng Zhang, Yan Ji, et al. "Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation." Nature Communications 13, no. 1 (December 3, 2022). http://dx.doi.org/10.1038/s41467-022-35250-0.
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AbstractTreg cells acquire distinct transcriptional properties to suppress specific inflammatory responses. Transcription characteristics of Treg cells are regulated by epigenetic modifications, the mechanism of which remains obscure. Here, we report that Setd2, a histone H3K36 methyltransferase, is important for the survival and suppressive function of Treg cells, especially those from the intestine. Setd2 supports GATA3+ST2+ intestinal thymic-derived Treg (tTreg) cells by facilitating the expression and reciprocal relationship of GATA3 and ST2 in tTreg cells. IL-33 preferentially boosts Th2 cells rather than GATA3+ Treg cells in Foxp3Cre-YFPSetd2 flox/flox mice, corroborating the constraint of Th2 responses by Setd2 expression in Treg cells. SETD2 sustains GATA3 expression in human Treg cells, and SETD2 expression is increased in Treg cells from human colorectal cancer tissues. Epigenetically, Setd2 regulates the transcription of target genes (including Il1rl1) by modulating the activity of promoters and intragenic enhancers where H3K36me3 is typically deposited. Our findings provide mechanistic insights into the regulation of Treg cells and intestinal immunity by Setd2.
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Jiang, Yuanbing, Xiaopu Zhou, Hiu Yi Wong, Li Ouyang, Fanny C. F. Ip, Vicky M. N. Chau, Shun-Fat Lau, et al. "An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease." Nature Aging, July 15, 2022. http://dx.doi.org/10.1038/s43587-022-00241-9.
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AbstractChanges in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.
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Gatti, Francesca, Sobuj Mia, Clara Hammarström, Nadine Frerker, Bjarte Fosby, Junbai Wang, Wojciech Pietka, et al. "Nuclear IL-33 restrains the early conversion of fibroblasts to an extracellular matrix-secreting phenotype." Scientific Reports 11, no. 1 (January 8, 2021). http://dx.doi.org/10.1038/s41598-020-80509-5.
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AbstractInterleukin (IL)-33 is a cytokine that appears to mediate fibrosis by signaling via its receptor ST2 (IL-33R/IL1RL1). It is also, however, a protein that after synthesis is sorted to the cell nucleus, where it appears to affect chromatin folding. Here we describe a novel role for nuclear IL-33 in regulating the fibroblast phenotype in murine kidney fibrosis driven by unilateral ureteral obstruction. Transcriptional profiling of IL-33-deficient kidneys 24 h after ligation revealed enhanced expression of fibrogenic genes and enrichment of gene sets involved in extracellular matrix formation and remodeling. These changes relied on intracellular effects of IL-33, because they were not reproduced by treatment with a neutralizing antibody to IL-33 that prevents IL-33R/ST2L receptor signaling nor were they observed in IL-33R/ST2-deficient kidneys. To further explore the intracellular function of IL-33, we established transcription profiles of human fibroblasts, observing that knockdown of IL-33 skewed the transcription profile from an inflammatory towards a myofibroblast phenotype, reflected in higher levels of COL3A1, COL5A1 and transgelin protein, as well as lower expression levels of IL6, CXCL8, CLL7 and CCL8. In conclusion, our findings suggest that nuclear IL-33 in fibroblasts dampens the initial profibrotic response until persistent stimuli, as enforced by UUO, can override this protective mechanism.
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Gatti, Francesca, Sobuj Mia, Clara Hammarström, Nadine Frerker, Bjarte Fosby, Junbai Wang, Wojciech Pietka, et al. "Nuclear IL-33 restrains the early conversion of fibroblasts to an extracellular matrix-secreting phenotype." Scientific Reports 11, no. 1 (January 8, 2021). http://dx.doi.org/10.1038/s41598-020-80509-5.
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AbstractInterleukin (IL)-33 is a cytokine that appears to mediate fibrosis by signaling via its receptor ST2 (IL-33R/IL1RL1). It is also, however, a protein that after synthesis is sorted to the cell nucleus, where it appears to affect chromatin folding. Here we describe a novel role for nuclear IL-33 in regulating the fibroblast phenotype in murine kidney fibrosis driven by unilateral ureteral obstruction. Transcriptional profiling of IL-33-deficient kidneys 24 h after ligation revealed enhanced expression of fibrogenic genes and enrichment of gene sets involved in extracellular matrix formation and remodeling. These changes relied on intracellular effects of IL-33, because they were not reproduced by treatment with a neutralizing antibody to IL-33 that prevents IL-33R/ST2L receptor signaling nor were they observed in IL-33R/ST2-deficient kidneys. To further explore the intracellular function of IL-33, we established transcription profiles of human fibroblasts, observing that knockdown of IL-33 skewed the transcription profile from an inflammatory towards a myofibroblast phenotype, reflected in higher levels of COL3A1, COL5A1 and transgelin protein, as well as lower expression levels of IL6, CXCL8, CLL7 and CCL8. In conclusion, our findings suggest that nuclear IL-33 in fibroblasts dampens the initial profibrotic response until persistent stimuli, as enforced by UUO, can override this protective mechanism.
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Wjst, Matthias. "Exome variants associated with asthma and allergy." Scientific Reports 12, no. 1 (December 5, 2022). http://dx.doi.org/10.1038/s41598-022-24960-6.
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AbstractThe mutational spectrum of asthma and allergy associated genes is not known although recent biobank based exome sequencing studies included these traits. We therefore conducted a secondary analysis of exome data from 281,104 UK Biobank samples for association of mostly rare variants with asthma, allergic rhinitis and atopic dermatitis. Variants of interest (VOI) were tabulated, shared genes annotated and compared to earlier genome-wide SNP association studies (GWAS), whole genome sequencing, exome and bisulfit sequencing studies. 354 VOI were significantly associated with asthma, allergic rhinitis and atopic dermatitis. They cluster mainly in two large regions on chromosome 6 and 17. After exclusion of the variants associated with atopic dermatitis and redundant variants, 321 unique VOI remain in 122 unique genes. 30 genes are shared among the 87 genes with increased and the 65 genes with decreased risk for allergic disease. 85% of genes identified earlier by common GWAS SNPs are not replicated here. Most identified genes are located in interferon ɣ and IL33 signaling pathway. These genes include already known but also new pharmacological targets, including the IL33 receptor ST2/IL1RL1, as well as TLR1, ALOX15, GSDMA, BTNL2, IL13 and IKZF3. Future pharmacological studies will need to included these VOI for stratification of the study population paving the way to individualized treatment.
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Zhang, Yichi, Haige Zhao, Qun Su, Cuili Wang, Hongjun Chen, Lingling Shen, Liang Ma, et al. "Novel Plasma Biomarker-Based Model for Predicting Acute Kidney Injury After Cardiac Surgery: A Case Control Study." Frontiers in Medicine 8 (January 14, 2022). http://dx.doi.org/10.3389/fmed.2021.799516.
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Introduction:Acute kidney injury (AKI) after cardiac surgery is independently associated with a prolonged hospital stay, increased cost of care, and increased post-operative mortality. Delayed elevation of serum creatinine (SCr) levels requires novel biomarkers to provide a prediction of AKI after cardiac surgery. Our objective was to find a novel blood biomarkers combination to construct a model for predicting AKI after cardiac surgery and risk stratification.Methods:This was a case-control study. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to Gene Expression Omnibus (GEO) dataset GSE30718 to seek potential biomarkers associated with AKI. We measured biomarker levels in venous blood samples of 67 patients with AKI after cardiac surgery and 59 control patients in two cohorts. Clinical data were collected. We developed a multi-biomarker model for predicting cardiac-surgery-associated AKI and compared it with a traditional clinical-factor-based model.Results:From bioinformatics analysis and previous articles, we found 6 potential plasma biomarkers for the prediction of AKI. Among them, 3 biomarkers, such as growth differentiation factor 15 (GDF15), soluble suppression of tumorigenicity 2 (ST2, IL1RL1), and soluble urokinase plasminogen activator receptor (uPAR) were found to have prediction ability for AKI (area under the curve [AUC] > 0.6) in patients undergoing cardiac surgery. They were then incorporated into a multi-biomarker model for predicting AKI (C-statistic: 0.84, Brier 0.15) which outperformed the traditional clinical-factor-based model (C-statistic: 0.73, Brier 0.16).Conclusion:Our research validated a promising plasma multi-biomarker model for predicting AKI after cardiac surgery.
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Haller, Paul M., Benedikt N. Beer, Andrew M. Tonkin, Stefan Blankenberg, and Johannes T. Neumann. "Role of Cardiac Biomarkers in Epidemiology and Risk Outcomes." Clinical Chemistry, November 23, 2020. http://dx.doi.org/10.1093/clinchem/hvaa228.
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Abstract Background The use of biomarkers associated with cardiovascular disease (CVD) is established for diagnostic purposes. Cardiac troponins, as specific markers of myocardial injury, and natriuretic peptides, reflecting myocardial dilation, are routinely used for diagnosis in clinical practice. In addition, a substantial body of research has shed light on the ability of biomarkers to reflect the risk of future major cardiovascular events. Among biomarkers, troponin and members of the natriuretic peptide family have been investigated extensively in the general population, in those at higher risk, and in patients with known CVD. Both biomarkers have been shown to contribute substantially to statistical models describing cardiovascular risk, in addition to and independently of important clinical characteristics. The more precise identification of individuals at risk by appropriate use of biomarkers might lead to an earlier initiation of preventive therapies and potentially avoid significant events. Content We summarize the current evidence concerning risk prediction using cardiac biomarkers at different stages in the development of CVD and provide examples of observational studies and large-scale clinical trials testing such application. Beyond the focus on troponin and natriuretic peptides, we also discuss other important and emerging biomarkers in the field with potential for such application, including growth differentiation factor-15, soluble ST2 (alias for IL1RL1 [interleukin 1 receptor like 1), and galectin-3. Summary Incorporating biomarkers in risk prediction models might allow more precise identification of individuals at risk. Among the various biomarkers, cardiac troponin appears to be the most promising for prediction of future cardiovascular events in a wide variety of patient populations.
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Jiang, Wenxi, Xue Wang, Pei Gao, Fengjuan Li, Ke Lu, Xin Tan, Shuai Zheng, et al. "Association of IL1R1 Coding Variant With Plasma-Level Soluble ST2 and Risk of Aortic Dissection." Frontiers in Cardiovascular Medicine 8 (August 2, 2021). http://dx.doi.org/10.3389/fcvm.2021.710425.
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Objective: Aortic dissection (AD) is characterized by an acute onset, rapid progress, and high mortality. Levels of soluble ST2 (sST2) on presentation are elevated in patients with acute AD, which can be used to discriminate AD patients from patients with chest pain. sST2 concentrations were found to be highly heritable in the general population. The aim of this study was to investigate the associations of variations in ST2-related gene expression with sST2 concentrations and AD risk.Methods: This case-control study involving a total of 2,277 participants were conducted, including 435 AD patients and age- and sex-matched 435 controls in the discovery stage, and 464 patients and 943 controls in the validation stage. Eight ST2-related genes were selected by systematic review. Tag single-nucleotide polymorphisms (SNPs) were screened out from the Chinese population of the 1,000 Genomes Database. Twenty-one ST2-related SNPs were genotyped, and plasma sST2 concentrations were measured.Results: In the discovery stage, rs13019803 located in IL1R1 was significantly associated with AD after Bonferroni correction (p = 0.0009) and was correlated with circulating sST2 levels in patients with type A AD(AAD) [log-sST2 per C allele increased by 0.180 (95%) CI: 0.002 – 0.357] but not in type B. Combining the two stages together, rs13019803C was associated with plasma sST2 level in AAD patients [log-sST2 increased by 0.141 (95% CI: 0.055–0.227) for per C allele]. Odds ratio of rs13019803 on the risk of AAD is 1.67 (95% CI: 1.33–2.09).Conclusions: The IL1R1 SNP rs13019803C is associated with higher sST2 levels and increased risk of AAD.
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Arias, Eugenia, Horacio Martinetto, Naomi Arakaki, Gustavo E. Sevlever, and Sebastian F. Ameriso. "Abstract WP141: Genetic Polymorphisms Influence Carotid Atherosclerosis." Stroke 48, suppl_1 (February 2017). http://dx.doi.org/10.1161/str.48.suppl_1.wp141.
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Introduction: Genetic susceptibility affects atherosclerosis in humans. Polymorphisms of genes of angiotensin-converting enzyme (ACE), lipoprotein APOE (APOE), IL1 receptor antagonist (IL1Ra) and myeloperoxidase (MPO) are associated with several components of atherosclerotic disease. We evaluated allelic and genotypic frequencies and their association with age at presentation, vascular risk factors, and presence of symptoms in subjects with carotid atherosclerosis. Methods: We studied Argentine patients with severe carotid atherosclerosis and controls from the general population. Age, vascular risk factors and presence of neurological symptoms were recorded. DNA was obtained from peripheral blood and PCR or PCR-RFLP were used to typify ACE, APOE, IL1Ra, and MPO genes. Allelic and genotypic frequencies were compared and genotypic susceptibility variants were established. Chi-square and good fit test were applied for differences between expected and observed frequencies. Results: There were 137 patients, 36 women and 101 men, aged 67±8 years. Symptomatic subjects younger than 60 years had higher frequency of the alleles ACE-DD, associated to vasoconstriction, endothelial proliferation, oxidation, and apoptosis (p<0.01); IL1RN-12/22, associated to inflammation and apoptosis (p<0.01); and MPO*GA/AA, associated to less oxidative response and proatherogenic (p<0.05). Subjects older than 60 years had a genetic profile similar to the general population without atherosclerosis, with similar prevalence of ACE-ID/II, IL1RN-11, and MPO-GG and a higher frequency of APOE23, 24 and 34m. Independent associations of ACE*D and IL1RN*2 with dyslipidemia and of MPO-GA and APOE-34 with hypertension were observed. Conclusions: Subjects with carotid atherosclerosis are genetically different from the general population. Carriers of certain gene variants were predominant among atherosclerotic subjects, suggesting susceptibility, and others were more prevalent in controls, suggesting protection. Some polymorphisms and their combinations are associated with occurrence of symptomatic disease at an earlier age. The genetic profile of older patients does not substantially differ from the general population.
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Díaz-Jiménez, David, Lucía Núñez, Marjorie De la Fuente, Karen Dubois-Camacho, Hugo Sepúlveda, Martín Montecino, Alejandro Torres-Riquelme, et al. "A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis." Scientific Reports 7, no. 1 (August 31, 2017). http://dx.doi.org/10.1038/s41598-017-10465-0.
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Arias, Eugenia, Naomi Arakaki, Horacio Martinetto, Gustavo E. Sevlever, and Sebastian F. Ameriso. "Abstract TP110: Helicobacter Pylori Infection and Genetic Factors as Determinants of Carotid Plaque Stability." Stroke 48, suppl_1 (February 2017). http://dx.doi.org/10.1161/str.48.suppl_1.tp110.
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Introduction: Little is known about the role of H pylori in human atherosclerosis. We have previously demonstrated its presence in carotid plaques, especially among asymptomatic patients, with prevalence of cag A-positive strains. Polymorphisms of genes of angiotensin-converting enzyme (ACE), lipoprotein APOE (APOE), IL1 receptor antagonist (IL1Ra) and myeloperoxidase (MPO) are associated with atherosclerosis. We evaluated the role of H pylori in certain features of carotid plaques and assessed allelic and genotypic frequencies and their association with H pylori infection and plaque characteristics. Methods: We studied 137 carotid plaques of patients undergoing endarterectomy. We categorized as stable those predominantly fibrous plaques with scarce inflammatory cells, intact cap and no hemorrhage and unstable those plaques with inflammation, thin cap, ruptured lipid core, thrombi and hemorrhage. We extracted genomic DNA and identified and typified H Pylori DNA. DNA was also obtained from peripheral blood and we identified allelic and genotypic frequencies and susceptibility variants of ACE, APOE, IL1Ra, and MPO genes. Fisher’s exact test (two-tailed) and good fit test were used. Results: There were 72 asymptomatic patients with 47 stable and 25 unstable plaques and 65 symptomatic patients with 13 stable and 52 unstable plaques (p<0.0001). H pylori infection was present in 48 of 60 stable plaques and 31 of 77 unstable plaques (p<0.0001). In addition, stable infected plaques more often carried the more virulent cag A strain. H pylori cag A-negative plaques had larger intima media complex thickness than cag A-positive and H pylori -negative plaques. Stable infected plaques were associated to alleles APOE-33 and IL1RN-11. Unstable noninfected plaques were associated to proatherogenic alleles ACE-DD, APOE*4, APOE*2, IL1RN*2, and MPO-GG. Conclusions: Histopathological features of plaque instability are associated to the presence of recent symptoms. H pylor i infection with the virulent cag A strain is highly prevalent in stable carotid plaques of asymptomatic subjects. Noninflammatory genotypes are present in stable infected plaques whereas proatherogenic polymorphisms are predominant in unstable noninfected plaques.
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Adamski, Mateusz G., Yan Li, Hua Yu, Erin Wagner, Sareen Amarjeet, Steve A. Soper, and Alison E. Baird. "Abstract 3259: Leukocyte Subset Specific Gene Expression In Acute Stroke Patients." Stroke 43, suppl_1 (February 2012). http://dx.doi.org/10.1161/str.43.suppl_1.a3259.
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Background: Alterations in gene expression in the peripheral blood of patients with acute stroke have been demonstrated using microarray technology. Whole blood and peripheral blood mononuclear cells (PBMCs) were used in prior studies in which panels of genes diagnostic for stroke were developed. We aimed to determine the cellular sources of alterations in gene expression by studying individual leukocyte subsets. Methods: The expression of four genes previously found to be upregulated in ischemic and hemorrhagic stroke (IL1R2, S100A9, ETS2 and F5) was measured in four leukocyte subsets: CD14+ monocytes, CD4+ T cell lymphocytes, CD20+ B cell lymphocytes and PBMCs. These four genes had been reported in at least two of the previously published stroke-related gene panels. Peripheral blood was obtained from six acute stroke patients (all <48 hours from symptom onset) and 6 age, race and sex matched control subjects. Leukocytes were separated from whole blood using density gradient centrifugation and column magnetic bead cell sorting. The purity of separated leukocyte subsets exceeded 90% and was verified with flow cytometry. Messenger RNA was isolated from each leukocyte subset and analyzed by two step RT PCR and qPCR. The expression of the four stroke-related genes was compared to the expression of a housekeeping gene (GAPDH). The relative expression of individual genes and of the 4 gene panel within cellular subsets was compared between stroke patients and control subjects. Results: Individually, IL1R2 and S100A9 were significantly over-expressed in stroke patients with a 10 fold increase for IL1R2 in PBMCs (p<0.05) and a 3 fold increase for S100A9 in the CD4+ T and CD20+ B lymphocyte subsets (p<0.05). When analyzed as a panel of four genes the expression of IL1R2, S100A9, ETS2 and F5 was significantly higher in both the CD4+ T lymphocytes (p<0.05) and CD20+ B lymphocytes (p<0.05) of stroke patients but not in the monocytes or the PBMCs. Conclusion: These results show the potential diagnostic value of selected genes from panels previously found in microarray studies in stroke patients. They also emphasize the value of panel analysis over that of single gene expression and the potential cellular specificity of alterations in gene expression. Analysis of whole blood and PBMCs alone may not reflect important dynamic changes in stroke-related gene expression.
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Becker, Kyra, Hunter Phillips, Ricahrd Lee, Patricia Tanzi, Dannielle Zierath, Kevin Cain, and Jonathan Weinstein. "Abstract TP114: Post-stroke Fatigue Is Linked To The IL1RN Polymorphism rs4251961." Stroke 44, suppl_1 (February 2013). http://dx.doi.org/10.1161/str.44.suppl_1.atp114.
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Background: Post-stroke fatigue (PSF) is common, but the biological basis of PSF is unknown. We explored the relationship between PSF, systemic inflammation and genetic polymorphisms that affect the immune response. Methods: In a substudy of a larger trial that evaluated the role of the immune response on stroke outcome, patients were asked about their level of fatigue at 30, 90, 180, and 365 days after ischemic stroke. (The degree fatigue of was quantified using the Fatigue Assessment Scale [FAS], with possible scores of 10 (minimal fatigue) to 50 (severe fatigue). Plasma cytokine concentrations were analyzed and patients genotyped for polymorphisms in the promoter of the interleukin-1 receptor antagonist (IL-1ra) gene (IL1RN; rs4251961). The minor allele (C) is associated with decreased IL-1ra in healthy adults in comparison with the major (T) allele. Results: Of patients for whom FAS scores were available (N=38), there were 16 (41%) with TT, 14 (36%) with CT and 8 (21%) with CC genotypes. The degree of fatigue (median [interquartile range]) was remarkably constant over time (22 [16, 29]) and tended to be higher in patients with a C allele (Figure). The FAS scores for patients with the minor C allele was 26 (17, 32) and was 18 in those without (13, 26; P=0.046). If fatigue is defined as an FAS score greater than the 75th percentile value for all patients (>29), 8/22 (36%) of patients with the C allele experienced fatigue while only 1/16 (6%) patients with TT did (P=0.031). Controlling for stroke severity, age and gender, the odds ratio (95% confidence interval) for developing fatigue (FAS>29) with a C allele was 9.96 (1.13-87.42; P=0.038). The concentration of IL-1ra did not differ among patients with the C allele and those without at any time point and was not associated with the FAS score. Conclusions: The rs4251961 polymorphism of IL1RN appears to be associated with PSF. This finding, and the relationship to systemic markers of inflammation, will need to be validated in a larger cohort.
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Alfaidi, Mabruka, Milla Reddick, Xinggui Shen, and Wayne Orr. "Abstract MP06: The Signaling Roles Of The Adaptor Protein Nck1 In Atherosclerosis." Arteriosclerosis, Thrombosis, and Vascular Biology 41, Suppl_1 (September 2021). http://dx.doi.org/10.1161/atvb.41.suppl_1.mp06.
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Rational: Alterations in hemodynamic shear stress (SS) at atherosclerosis-prone sites promotes endothelial activation, characterized by nuclear factor-κB (NF-κB)-driven expression of cell adhesion molecules that mediate leukocyte homing. In addition, proinflammatory cytokines (e.g. IL-1β) promote NF-κB-dependent endothelial activation. While the recent CANTOS trial using an IL-1β antagonist highlights the potential for treating atherogenic inflammation beyond lipid lowering therapies alone, our understanding of how endothelial activation contributes to this effect remains limited. Methodology & Results: We identified the signaling adaptor Nck1 as a critical regulator of atherogenic endothelial activation. Endothelial cells deficient in Nck1 lack SS-induced NF-κB activation and proinflammatory gene expression. Additionally, we demonstrated an interaction between Nck1 and IL-1β signaling in response to SS, showing that SS activates the IL-1β receptor (IL1R1) signaling partner IRAK-1 in a Nck1-dependent manner both in vitro and in vivo . Mechanistically, point mutation analysis suggest a critical role for the Nck1 SH2 domain (phosphotyrosine binding domain) in mediating these effects. Nck1 affinity pulling down and mass spectrometry identified multiple downstream effectors of IL-1 pathway. In vivo, Global Nck1 knockout mice show reduced atherosclerosis characterized by diminished macrophage and smooth muscle incorporation and bone marrow chimeras suggest non-hematopoietic Nck1 mediates this response. Conclusions: A recent GWAS analysis linked Nck1 to coronary artery disease, underscoring its importance to human disease. Therefore, our data suggest that Nck1 mediates the formation of IL-1-related signaling complexes to induce atherogenic endothelial activation, and selective inhibition of Nck1 or its critical domains will allow efficient inhibition of atherosclerosis in humans.
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Fields, James K., Kyle Kihn, Gabriel S. Birkedal, Erik H. Klontz, Kjell Sjöström, Sebastian Günther, Robert Beadenkopf, et al. "Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor." Frontiers in Immunology 12 (December 24, 2021). http://dx.doi.org/10.3389/fimmu.2021.779100.
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Interleukin-1 (IL-1) family cytokines are potent mediators of inflammation, acting to coordinate local and systemic immune responses to a wide range of stimuli. Aberrant signaling by IL-1 family cytokine members, however, is linked to myriad inflammatory syndromes, autoimmune conditions and cancers. As such, blocking the inflammatory signals inherent to IL-1 family signaling is an established and expanding therapeutic strategy. While several FDA-approved IL-1 inhibitors exist, including an Fc fusion protein, a neutralizing antibody, and an antagonist cytokine, none specifically targets the co-receptor IL-1 receptor accessory protein (IL-1RAcP). Most IL-1 family cytokines form productive signaling complexes by binding first to their cognate receptors – IL-1RI for IL-1α and IL-1β; ST2 for IL-33; and IL-36R for IL-36α, IL-36β and IL-36γ – after which they recruit the shared secondary receptor IL-1RAcP to form a ternary cytokine/receptor/co-receptor complex. Recently, IL-1RAcP was identified as a biomarker for both AML and CML. IL-1RAcP has also been implicated in tumor progression in solid tumors and an anti-IL1RAP antibody (nadunolimab, CAN04) is in phase II clinical studies in pancreatic cancer and non-small cell lung cancer (NCT03267316). As IL-1RAcP is common to all of the abovementioned IL-1 family cytokines, targeting this co-receptor raises the possibility of selective signaling inhibition for different IL-1 family cytokines. Indeed, previous studies of IL-1β and IL-33 signaling complexes have revealed that these cytokines employ distinct mechanisms of IL-1RAcP recruitment even though their overall cytokine/receptor/co-receptor complexes are structurally similar. Here, using functional, biophysical, and structural analyses, we show that antibodies specific for IL-1RAcP can differentially block signaling by IL-1 family cytokines depending on the distinct IL-1RAcP epitopes that they engage. Our results indicate that targeting a shared cytokine receptor is a viable therapeutic strategy for selective cytokine signaling inhibition.