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Fujimori, Takeshi, Daisuke Ogawa, Kenta Suzuki, Masaaki Kochi, Yuki Shibayama, Masaki Okada, Keisuke Miyake, Akira Nishiyama, and Takashi Tamiya. "ET-04 MOLECULAR TARGETED THERAPY AGAINST (PRO)RENIN RECEPTOR FOR GLIOBLASTOMA." Neuro-Oncology Advances 1, Supplement_2 (December 2019): ii8—ii9. http://dx.doi.org/10.1093/noajnl/vdz039.038.
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Abstract INTRODUCTION (Pro)renin receptor(PRR) is part of the Wnt receptor complex. Wnt/β-catenin signaling pathway (Wnt signaling) plays important role in pathogenesis and self-renewal of glioblastoma (GBM), or differentiation of glioma stem cell. We previously reported that PRR activate Wnt signaling, PRR expression correlated with malignancy of glioma, and treatment with PRR siRNA reduced the proliferative capacity. This time, we have developed monoclonal antibodies against PRR and examined their effects in GBM. MATERIAL AND METHODS We used GBM cell line (U251MG and U87MG) and primary human glioma stem cell line (MGG23). Glioma stem-like cells were cultured and isolated by neurosphere method from U251MG and U87MG. PRR antibody was made targeting the extracellular domain of the PRR with rat lymph node method. WST-1 assay or MTT assay were performed to determine the cell proliferation. Apoptosis was examined by FITC labeled annexin V and propidium iodide with flow cytometry. We analyzed molecules of Wnt signaling and stem cell markers with qRT-PCR. RESULTS We observed that PRR antibody significantly reduced cell proliferation, decreased sphere formation. Antibody suppressed cell adherent in stem-like cell. Flow cytometry showed that antibody induced apoptosis. Antibody inhibited Wnt signaling and stem cell markers. CONCLUSIONS PRR antibody reduced cell proliferation and induced apoptosis through Wnt signaling. PRR antibody also suppressed stemness. Our results demonstrated that PRR was a potential target for future glioma therapy.
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Sellge, Gernot, and Thomas A. Kufer. "PRR-signaling pathways: Learning from microbial tactics." Seminars in Immunology 27, no. 2 (March 2015): 75–84. http://dx.doi.org/10.1016/j.smim.2015.03.009.
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Neerukonda, Sabari Nath, and Upendra Katneni. "Avian Pattern Recognition Receptor Sensing and Signaling." Veterinary Sciences 7, no. 1 (January 27, 2020): 14. http://dx.doi.org/10.3390/vetsci7010014.
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Pattern recognition receptors (PRRs) are a class of immune sensors that play a critical role in detecting and responding to several conserved patterns of microorganisms. As such, they play a major role in the maintenance of immune homeostasis and anti-microbial defense. Fundamental knowledge pertaining to the discovery of PRR functions and their ligands continue to advance the understanding of immune system and disease resistance, which led to the rational design and/or application of various PRR ligands as vaccine adjuvants. In addition, the conserved nature of many PRRs throughout the animal kingdom has enabled the utilization of the comparative genomics approach in PRR identification and the study of evolution, structural features, and functions in many animal species including avian. In the present review, we focused on PRR sensing and signaling functions in the avian species, domestic chicken, mallard, and domestic goose. In addition to summarizing recent advances in the understanding of avian PRR functions, the present review utilized a comparative biology approach to identify additional PRRs, whose functions have been well studied in mammalians but await functional characterization in avian.
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Lahiri, Amit, Matija Hedl, and Clara Abraham. "MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation." Proceedings of the National Academy of Sciences 112, no. 33 (August 3, 2015): 10461–66. http://dx.doi.org/10.1073/pnas.1501752112.
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Inflammatory bowel disease (IBD) is characterized by dysregulated host:microbial interactions and cytokine production. Host pattern recognition receptors (PRRs) are critical in regulating these interactions. Multiple genetic loci are associated with IBD, but altered functions for most, including in the rs713875 MTMR3/HORMAD2/LIF/OSM region, are unknown. We identified a previously undefined role for myotubularin-related protein 3 (MTMR3) in amplifying PRR-induced cytokine secretion in human macrophages and defined MTMR3-initiated mechanisms contributing to this amplification. MTMR3 decreased PRR-induced phosphatidylinositol 3-phosphate (PtdIns3P) and autophagy levels, thereby increasing PRR-induced caspase-1 activation, autocrine IL-1β secretion, NFκB signaling, and, ultimately, overall cytokine secretion. This MTMR3-mediated regulation required the N-terminal pleckstrin homology-GRAM domain and Cys413 within the phosphatase domain of MTMR3. In MTMR3-deficient macrophages, reducing the enhanced autophagy or restoring NFκB signaling rescued PRR-induced cytokines. Macrophages from rs713875 CC IBD risk carriers demonstrated increased MTMR3 expression and, in turn, decreased PRR-induced PtdIns3P and autophagy and increased PRR-induced caspase-1 activation, signaling, and cytokine secretion. Thus, the rs713875 IBD risk polymorphism increases MTMR3 expression, which modulates PRR-induced outcomes, ultimately leading to enhanced PRR-induced cytokines.
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Timmermans, Kim, Theo S. Plantinga, Matthijs Kox, Michiel Vaneker, Gert Jan Scheffer, Gosse J. Adema, Leo A. B. Joosten, and Mihai G. Netea. "Blueprints of Signaling Interactions between Pattern Recognition Receptors: Implications for the Design of Vaccine Adjuvants." Clinical and Vaccine Immunology 20, no. 3 (January 23, 2013): 427–32. http://dx.doi.org/10.1128/cvi.00703-12.
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ABSTRACTInnate immunity activation largely depends on recognition of microorganism structures by Pattern Recognition Receptors (PRRs). PRR downstream signaling results in production of pro- and anti-inflammatory cytokines and other mediators. Moreover, PRR engagement in antigen-presenting cells initiates the activation of adaptive immunity. Recent reports suggest that for the activation of innate immune responses and initiation of adaptive immunity, synergistic effects between two or more PRRs are necessary. No systematic analysis of the interaction between the major PRR pathways were performed to date. In this study, a systematical analysis of the interactions between PRR signaling pathways was performed. PBMCs derived from 10 healthy volunteers were stimulated with either a single PRR ligand or a combination of two PRR ligands. Known ligands for the major PRR families were used: Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), and RigI-helicases. After 24 h of incubation, production of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and IL-10 was measured in supernatants by enzyme-linked immunosorbent assay (ELISA). The consistency of the PRR interactions (both inhibitory and synergistic) between the various individuals was assessed. A number of PRR-dependent signaling interactions were found to be consistent, both between individuals and with regard to multiple cytokines. The combinations of TLR2 and NOD2, TLR5 and NOD2, TLR5 and TLR3, and TLR5 and TLR9 acted as synergistic combinations. Surprisingly, inhibitory interactions between TLR4 and TLR2, TLR4 and Dectin-1, and TLR2 and TLR9 as well as TLR3 and TLR2 were observed. These consistent signaling interactions between PRR combinations may represent promising targets for immunomodulation and vaccine adjuvant development.
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Zhang, Zhongqin, Chika Tateda, Shang-Chuan Jiang, Jay Shrestha, Joanna Jelenska, DeQuantarius J. Speed, and Jean T. Greenberg. "A Suite of Receptor-Like Kinases and a Putative Mechano-Sensitive Channel Are Involved in Autoimmunity and Plasma Membrane–Based Defenses in Arabidopsis." Molecular Plant-Microbe Interactions® 30, no. 2 (February 2017): 150–60. http://dx.doi.org/10.1094/mpmi-09-16-0184-r.
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In plants, cell surface pattern recognition receptors (PRRs) provide a first line of defense against pathogens. Although each PRR recognizes a specific ligand, they share common signaling outputs, such as callose and other cell wall–based defenses. Several PRRs are also important for callose induction in response to the defense signal salicylic acid (SA). The extent to which common components are needed for PRR signaling outputs is not known. The gain-of-function Arabidopsis mutant of ACCELERATED CELL DEATH6 (ACD6) acd6-1 shows constitutive callose production that partially depends on PRRs. ACD6-1 (and ACD6) forms complexes with the PRR FLAGELLIN SENSING2, and ACD6 is needed for responses to several PRR ligands. Thus, ACD6-1 could serve as a probe to identify additional proteins important for PRR-mediated signaling. Candidate signaling proteins (CSPs), identified in our proteomic screen after immunoprecipitation of hemagglutinin (HA)-tagged ACD6-1, include several subfamilies of receptor-like kinase (RLK) proteins and a MECHANO-SENSITIVE CHANNEL OF SMALL CONDUCTANCE-LIKE 4 (MSL4). In acd6-1, CSPs contribute to autoimmunity. In wild type, CSPs are needed for defense against bacteria and callose responses to two or more microbial-derived patterns and an SA agonist. CSPs may function to either i) promote the assembly of signaling complexes, ii) regulate the output of known PRRs, or both.
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Buchholz, Kerry R., and Richard S. Stephens. "The Cytosolic Pattern Recognition Receptor NOD1 Induces Inflammatory Interleukin-8 during Chlamydia trachomatis Infection." Infection and Immunity 76, no. 7 (April 21, 2008): 3150–55. http://dx.doi.org/10.1128/iai.00104-08.
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ABSTRACT Inflammation is a hallmark of chlamydial infections, but how inflammatory cytokines are induced is not well understood. Pattern recognition receptors (PRR) of the host innate immune system recognize pathogen molecules and activate intracellular signaling pathways that modulate immune responses. The role of PRR such as Toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD) proteins in the endogenous interleukin-8 (IL-8) response induced during Chlamydia trachomatis infection is not known. We hypothesized that a PRR is essential for the IL-8 response induced by C. trachomatis infection. RNA interference was used to knock down the TLR signaling partner MyD88 as well as NOD1 and its signaling molecule receptor-interacting protein 2 (RIP2). IL-8 induced at 30 h postinfection by C. trachomatis was dependent on NOD1 signaling through RIP2; however, the IL-8 response was independent of MyD88-dependent TLR signaling. Activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase cellular signaling pathway, which is essential for up-regulation of IL-8 in response to C. trachomatis infection, was independent of NOD1 or RIP2. We conclude that the endogenous IL-8 response induced by C. trachomatis infection is dependent upon NOD1 PRR signaling through RIP2 as part of a signal system requiring multiple inputs for optimal IL-8 induction. Since ERK is not activated through this pathway, a concomitant interaction between the host and bacteria is additionally required for full activation of the endogenous IL-8 response.
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Beitia, Maider, Jon Danel Solano-Iturri, Peio Errarte, Julio Calvete-Candenas, Alberto Loizate, Mari Carmen Etxezarraga, Begoña Sanz, and Gorka Larrinaga. "(Pro)renin Receptor Expression Increases throughout the Colorectal Adenoma—Adenocarcinoma Sequence and It Is Associated with Worse Colorectal Cancer Prognosis." Cancers 11, no. 6 (June 24, 2019): 881. http://dx.doi.org/10.3390/cancers11060881.
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(Pro)renin receptor (PRR) is a protein that takes part in several signaling pathways such as Renin Angiotensin System and Wnt signalling. Its biological role has recently been related to cancer progression and in this study, we investigated its relevance in colorectal cancer (CRC). To that end, we analysed the immunohistochemical expression of PRR in adenomatous polyps and CRCs from the same patients (n = 42), and in primary tumours and nodal and liver metastases from advanced CRC patients (n = 294). In addition, the soluble fraction of PRR was measured by ELISA in plasma samples from 161 CRC patients. The results showed that PRR expression was gradually augmented along the uninvolved mucosa–adenoma–adenocarcinoma sequence. Besides, the stronger expression of PRR in primary tumours was markedly associated with local tumour extent and the onset of metastases. Moreover, PRR expression in both primary and distant metastases was associated with worse 5- and 10-year survival of CRC patients. Plasmatic PRR levels did not change with respect to controls and were not associated with CRC aggressiveness. These results suggest a key role of PRR in the development and progression of CRC and a potential use of this protein as a new prognostic biomarker and/or therapeutic target for this disease.
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Kouchi, Masaaki, Yuki Shibayama, Daisuke Ogawa, Keisuke Miyake, Akira Nishiyama, and Takashi Tamiya. "(Pro)renin receptor is crucial for glioma development via the Wnt/β-catenin signaling pathway." Journal of Neurosurgery 127, no. 4 (October 2017): 819–28. http://dx.doi.org/10.3171/2016.9.jns16431.
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OBJECTIVEThe (pro)renin receptor (PRR) plays an essential role in the early development of the central nervous system by activating the Wnt/β-catenin signaling pathway. The authors investigated the potential role of the PRR in the pathogenesis of glioma.METHODSThe authors performed immunohistochemical analysis to detect both the PRR and isocitrate dehydrogenase 1 with mutations involving arginine 132 (IDH1R132H) in paraffin sections of 31 gliomas. Expression of the PRR and Wnt pathway components in cultured human glioma cell lines (U251MG, U87MG, and T98G) was measured using Western blotting. The effects of PRR short interfering RNA (siRNA) on glioma cell proliferation (WST-1 assay and direct cell counting) and apoptosis (flow cytometry and the caspase-3 assay) were also examined.RESULTSPRR expression was significantly higher in glioblastoma than in normal tissue or in lower grade glioma, regardless of IDH1R132H mutation. PRR expression was also higher in human glioblastoma cell lines than in human astrocytes. PRR expression showed a significant positive correlation with the Ki-67 labeling index, while it had a significant negative correlation with the survival time of glioma patients. Treatment with PRR siRNA significantly reduced expression of Wnt2, activated β-catenin, and cyclin D1 by human glioblastoma cell lines, and it reduced the proliferative capacity of these cell lines and induced apoptosis.CONCLUSIONSThis is the first evidence that the PRR has an important role in development of glioma by aberrant activation of the Wnt/β-catenin signaling pathway. This receptor may be both a prognostic marker and a therapeutic target for glioma.
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Fujimori, Takeshi, Daisuke Oagawa, Takahiro Kanda, Kenta Suzuki, Saki Shibayama, Keisuke Miyake, Akira Nishiyama, and Takashi Tamiya. "CBMS-12 Pro renin receptor antibody regulates glioblastoma stemness." Neuro-Oncology Advances 2, Supplement_3 (November 1, 2020): ii5. http://dx.doi.org/10.1093/noajnl/vdaa143.019.
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Abstract Objective: Glioblastoma multiforme (GBM) is characterized by a strong self-renewal potential and poor differentiated state. We previously reported that (pro)renin receptor (PRR) was a potential target for glioma therapy by silencing the gene of PRR. Here, we have developed the monoclonal antibody of PRR and examined their effects on GBM. Materials and methods: We performed immunohistochemical analysis to detect the protein expression of PRR and SOX-2 in human sample of 56 gliomas. We used human glioma cell lines (U251MG and U87MG) and glioma stem cell line (MGG23) in vitro study. PRR antibody was designed to target the extracellular domain of the PRR with the rat lymph node method. Expression of the Wnt signaling components and stem marker (SOX-2, Oct3/4) in human glioma cell lines and glioma stem cell line treated with PRR antibody were measured using Western blotting. The effects of PRR antibody on cell proliferation, sphere formation, apoptosis, invasion were also examined. Subcutaneous xenografts with U87MG were induced in nude mice. Results: PRR expression showed a positive correlation with SOX-2 expression in glioma samples. Treatment with PRR antibody significantly reduced expression of Wnt signaling components and stem marker. We observed that PRR antibody significantly reduced cell proliferation and decreased sphere formation. Furthermore, PRR antibody suppressed invasion and induced apoptosis. In a subcutaneous U87MG xenograft model, systemic administration of the PRR antibody significantly reduced the size of the tumor volume. Conclusion: PRR has important role for the maintenance of stem cells and contribute to stem cell proliferation. PRR antibody inhibits cell proliferation and cell invasion and induces apoptosis. Treatment with PRR antibody could be an attractive therapeutic strategy for GBM.
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D. Sundarasen, Sheela Devi. "Institutional characteristics, signaling variables and IPO initial returns." PSU Research Review 3, no. 1 (April 8, 2019): 29–49. http://dx.doi.org/10.1108/prr-10-2016-0003.
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Purpose This paper aims to provide empirical evidence on the extent of alteration institutional characteristics, i.e. legal origin and corruption levels, may have on the signaling effects of auditors’ reputation, underwriters’ reputation and ownership retention on initial public offering (IPO) initial returns in OECD countries. Design/methodology/approach Cross-sectional data composed of 6,182 IPOs from 30 OECD countries are used for 2003-2012. Ordinary least square with multiple linear regressions is used to test the hypotheses. Findings The findings indicate that the legal framework and corruption level of a country alters the signaling effects of underwriters’ reputation, auditors’ reputation and ownership retention in an IPO environment. These three variables mitigate information asymmetry, signal firm value to potential investors and ultimately decrease IPO initial returns. This relationship is more significant in the civil law countries. Corruption levels negatively moderate the relationship in the common law and Scandinavian civil law countries but have no significance in the German and French civil law countries, indicating the importance of the signaling variables in these two civil law countries. Originality/value This study examines the extent of the alterations that the legal framework and the corruption levels cause to the signaling relationship between auditors’ reputation, underwriters’ reputation and ownership retention on IPO initial returns in selected OECD countries.
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Song, Renfang, Adam Janssen, Yuwen Li, Samir El-Dahr, and Ihor V. Yosypiv. "Prorenin receptor controls renal branching morphogenesis via Wnt/β-catenin signaling." American Journal of Physiology-Renal Physiology 312, no. 3 (March 1, 2017): F407—F417. http://dx.doi.org/10.1152/ajprenal.00563.2016.
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The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump H+-ATPase. Renal branching morphogenesis, defined as growth and branching of the ureteric bud (UB), is essential for mammalian kidney development. Previously, we demonstrated that conditional ablation of the PRR in the UB in PRRUB−/− mice causes severe defects in UB branching, resulting in marked kidney hypoplasia at birth. Here, we investigated the UB transcriptome using whole genome-based analysis of gene expression in UB cells, FACS-isolated from PRRUB−/−, and control kidneys at birth (P0) to determine the primary role of the PRR in terminal differentiation and growth of UB-derived collecting ducts. Three genes with expression in UB cells that previously shown to regulate UB branching morphogenesis, including Wnt9b, β-catenin, and Fgfr2, were upregulated, whereas the expression of Wnt11, Bmp7, Etv4, and Gfrα1 was downregulated. We next demonstrated that infection of immortalized UB cells with shPRR in vitro or deletion of the UB PRR in double-transgenic PRRUB−/−/ BatGal+ mice, a reporter strain for β-catenin transcriptional activity, in vivo increases β-catenin activity in the UB epithelia. In addition to UB morphogenetic genes, the functional groups of differentially expressed genes within the downregulated gene set included genes involved in molecular transport, metabolic disease, amino acid metabolism, and energy production. Together, these data demonstrate that UB PRR performs essential functions during UB branching and collecting duct morphogenesis via control of a hierarchy of genes that control UB branching and terminal differentiation of the collecting duct cells.
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Kawano, Yoji, and Ko Shimamoto. "Early signaling network in rice PRR-mediated and R-mediated immunity." Current Opinion in Plant Biology 16, no. 4 (August 2013): 496–504. http://dx.doi.org/10.1016/j.pbi.2013.07.004.
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Ramkumar, Nirupama, and Donald E. Kohan. "The nephron (pro)renin receptor: function and significance." American Journal of Physiology-Renal Physiology 311, no. 6 (December 1, 2016): F1145—F1148. http://dx.doi.org/10.1152/ajprenal.00476.2016.
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The (pro)renin receptor (PRR) is a multifunctional protein that is part of the renin-angiotensin system and is an important accessory molecule for the vacuolar H+-ATPase. The PRR is widely expressed in the kidney with relatively high abundance in the distal nephron. Determining the physiological relevance of the PRR has been challenging due to early lethality in whole animal and cell-specific PRR knockout models. Recently, viable renal cell-specific PRR knockout mice have been developed; these studies suggest that PRR in the nephron can modulate renal function via angiotensin II (ANG II)-dependent and -independent cell signaling pathways. In this mini-review, we highlight new developments in nephron PRR function in health and in pathophysiological conditions.
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McMillan, Jourdan K. P., Patrick O’Donnell, and Sandra P. Chang. "Pattern recognition receptor ligand-induced differentiation of human transitional B cells." PLOS ONE 17, no. 8 (August 30, 2022): e0273810. http://dx.doi.org/10.1371/journal.pone.0273810.
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B cells represent a critical component of the adaptive immune response whose development and differentiation are determined by antigen-dependent and antigen-independent interactions. In this study, we explored the effects of IL-4 and pattern-recognition receptor (PRR) ligands on B cell development and differentiation by investigating their capacity to drive the in vitro maturation of human transitional B cells. In the presence of IL-4, ligands for TLR7/8, TLR9, and NOD1 were effective in driving the in vitro maturation of cord blood transitional B cells into mature, naïve B cells as measured by CD23 expression, ABCB1 transporter activation and upregulation of sIgM and sIgD. In addition, several stimulation conditions, including TLR9 ligand alone, favored an expansion of CD27+ IgM memory B cells. Transitional B cells stimulated with TLR7/8 ligand + IL-4 or TLR9 ligand, with or without IL-4, induced a significant subpopulation of CD23+CD27+ B cells expressing high levels of sIgM and sIgD, a minor B cell subpopulation found in human peripheral blood. These studies illustrate the heterogeneity of the B cell populations induced by cytokine and PRR ligand stimulation. A comparison of transitional and mature, naïve B cells transcriptomes to identify novel genes involved in B cell maturation revealed that mature, naïve B cells were less transcriptionally active than transitional B cells. Nevertheless, a subset of differentially expressed genes in mature, naïve B cells was identified including genes associated with the IL-4 signaling pathway, PI3K signaling in B lymphocytes, the NF-κB signaling pathway, and the TNFR superfamily. When transitional B cells were stimulated in vitro with IL-4 and PRR ligands, gene expression was found to be dependent on the nature of the stimulants, suggesting that exposure to these stimulants may alter the developmental fate of transitional B cells. The influence of IL-4 and PRR signaling on transitional B cell maturation illustrates the potential synergy that may be achieved when certain PRR ligands are incorporated as adjuvants in vaccine formulations and presented to developing B cells in the context of an inflammatory cytokine environment. These studies demonstrate the potential of the PRR ligands to drive transitional B cell differentiation in the periphery during infection or vaccination independently of antigen mediated BCR signaling.
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Johnson, Lexus, Carl H. June, and Andy J. Minn. "Intratumoral Localization of Pattern Recognition Receptor Signaling Informs CAR T Cell Design." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 134.4. http://dx.doi.org/10.4049/jimmunol.202.supp.134.4.
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Abstract Immune therapies have significantly improved outcomes for cancer patients with poor prognosis, but mechanisms that underlie response or resistance to therapy remain elusive. Type I and Type II interferon signaling is required for immune activation but is also known to drive programs of tumor-intrinsic resistance. We propose that activation of pattern recognition receptor (PRR) signaling in specific cellular compartments underlies this seemingly contradictory observation. We have recently identified the highly structured RNA RN7SL1 (7SL) as a novel intratumoral PAMP (pathogen associated molecular pattern) capable of activating PRR signaling. When over-expressed in tumor cells, the resulting tumors are resistant to immune checkpoint blockade (ICB) therapy. However, 7SL is stimulatory to primary human DCs, and improves T cell priming in vitro. Furthermore, direct intratumoral injection of 7SL improves immune activation and response to ICB in vivo. Thus, we propose the localization of PAMP recognition and PRR signaling may represent an important determinant of response to ICB therapy. Based on this finding, we have developed a CAR T cell capable of producing 7SL in the tumor microenvironment, as well as a fully syngeneic B16 solid tumor model for CAR T cell therapy. Murine 7SL-CAR T cells control tumors more robustly than controls and synergize with ICB. Importantly, this effect is dependent on endogenous T cells, indicating that 7SL-CAR T cells are jump-starting an endogenous polyclonal anti-tumor immune response. In total, this represents a novel insight into the role of PRR signaling in tumors and leverages the findings to create a therapy with potential to serve patients that are currently refractory to CAR-T or ICB therapies alone.
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Fabits, Markus, Vladimir Gonçalves Magalhães, Baca Chan, Virginie Girault, Endrit Elbasani, Elisa Rossetti, Eirikur Saeland, et al. "The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription." Microorganisms 8, no. 6 (May 26, 2020): 790. http://dx.doi.org/10.3390/microorganisms8060790.
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The rapid activation of pattern recognition receptor (PRR)-mediated type I interferon (IFN) signaling is crucial for the host response to infection. In turn, human cytomegalovirus (HCMV) must evade this potent response to establish life-long infection. Here, we reveal that the HCMV tegument protein UL35 antagonizes the activation of type I IFN transcription downstream of the DNA and RNA sensors cGAS and RIG-I, respectively. We show that ectopic expression of UL35 diminishes the type I IFN response, while infection with a recombinant HCMV lacking UL35 induces an elevated type I IFN response compared to wildtype HCMV. With a series of luciferase reporter assays and the analysis of signaling kinetics upon HCMV infection, we observed that UL35 downmodulates PRR signaling at the level of the key signaling factor TANK-binding kinase 1 (TBK1). Finally, we demonstrate that UL35 and TBK1 co-immunoprecipitate when co-expressed in HEK293T cells. In addition, we show that a previously reported cellular binding partner of UL35, O-GlcNAc transferase (OGT), post-translationally GlcNAcylates UL35, but that this modification is not required for the antagonizing effect of UL35 on PRR signaling. In summary, we have identified UL35 as the first HCMV protein to antagonize the type I IFN response at the level of TBK1, thereby enriching our understanding of how this important herpesvirus escapes host immune responses.
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Rutkowsky, Jennifer M., Trina A. Knotts, Kikumi D. Ono-Moore, Colin S. McCoin, Shurong Huang, Dina Schneider, Shamsher Singh, Sean H. Adams, and Daniel H. Hwang. "Acylcarnitines activate proinflammatory signaling pathways." American Journal of Physiology-Endocrinology and Metabolism 306, no. 12 (June 15, 2014): E1378—E1387. http://dx.doi.org/10.1152/ajpendo.00656.2013.
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Incomplete β-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and long-chain acylcarnitines (by-products of incomplete β-oxidation) are elevated in T2DM and insulin resistance. In a previous study, we reported that mixed d,l isomers of C12- or C14-carnitine induced an NF-κB-luciferase reporter gene in RAW 264.7 cells, suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant l-acylcarnitines activate classical proinflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of cyclooxygenase-2 in a chain length-dependent manner in RAW 264.7 cells. l-C14 carnitine (5–25 μM), used as a representative acylcarnitine, stimulated the expression and secretion of proinflammatory cytokines in a dose-dependent manner. Furthermore, l-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many proinflammatory signaling pathways including PRRs. Knockdown of MyD88, a key cofactor in PRR signaling and inflammation, blunted the proinflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, l-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking Toll-like receptors (TLR)2 and -4, and did not activate reporter constructs in TLR overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified.
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Huang, Jiqian, and Helmy M. Siragy. "Regulation of (Pro)Renin Receptor Expression by Glucose-Induced Mitogen-Activated Protein Kinase, Nuclear Factor-κB, and Activator Protein-1 Signaling Pathways." Endocrinology 151, no. 7 (May 5, 2010): 3317–25. http://dx.doi.org/10.1210/en.2009-1368.
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Renal (pro)renin receptor (PRR) expression is increased in diabetes. The exact mechanisms involved in this process are not well established. We hypothesized that high glucose up-regulates PRR through protein kinase C (PKC)-Raf-ERK and PKC-c-Jun N-terminal kinase (JNK)-c-Jun signaling pathways. Rat mesangial cells exposed to 30 mmd-glucose demonstrated significant increase in PRR mRNA and protein expression, intracellular phosphorylation of Raf-1 (Y340/341), ERK, JNK, nuclear factor-κB (NF-κB) p65 (S536) and c-Jun (S63). By chromatin immunoprecipitation assay and EMSA, high glucose induced more functional NF-κB and activator protein (AP)-1 dimers bound to corresponding cis-regulatory elements in the predicted PRR promoter to up-regulate PRR transcription. Conventional and novel PKC inhibitors Chelerythrine and Rottlerin, Raf-1 inhibitor GW5074, MEK1/2 inhibitor U0126, JNK inhibitor SP600125, NF-κB inhibitor Quinazoline, and AP-1 inhibitor Curcumin, respectively, attenuated glucose-induced PRR up-regulation. Chelerythrine and Rottlerin also inhibited glucose-induced phosphorylation of Raf-1 (Y340/341), ERK1/2, JNK, NF-κB p65 (S536), and c-Jun (S63). GW5074 and U0126 inhibited the phosphorylation of ERK1/2 and NF-κB p65 (S536). SP600125 inhibited phosphorylation of NF-κB p65 (S536) and c-Jun (S63). We conclude that high glucose up-regulates the expression of PRR through mechanisms dependent on both PKC-Raf-ERK and PKC-JNK-c-Jun signaling pathways. NF-κB and AP-1 are involved in high-glucose-induced PRR up-regulation in rat mesangial cells.
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Li, Wencheng, Jiao Liu, Sean L. Hammond, Ronald B. Tjalkens, Zubaida Saifudeen, and Yumei Feng. "Angiotensin II regulates brain (pro)renin receptor expression through activation of cAMP response element-binding protein." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 309, no. 2 (July 15, 2015): R138—R147. http://dx.doi.org/10.1152/ajpregu.00319.2014.
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We reported that brain (pro)renin receptor (PRR) expression levels are elevated in DOCA-salt-induced hypertension; however, the underlying mechanism remained unknown. To address whether ANG II type 1 receptor (AT1R) signaling is involved in this regulation, we implanted a DOCA pellet and supplied 0.9% saline as the drinking solution to C57BL/6J mice. Sham pellet-implanted mice that were provided regular drinking water served as controls. Concurrently, mice were intracerebroventricularly infused with the AT1R blocker losartan, angiotensin-converting-enzyme inhibitor captopril, or artificial cerebrospinal fluid for 3 wk. Intracerebroventricular infusion of losartan or captopril attenuated DOCA-salt-induced PRR mRNA elevation in the paraventricular nucleus of the hypothalamus, suggesting a role for ANG II/AT1R signaling in regulating PRR expression during DOCA-salt hypertension. To test which ANG II/AT1R downstream transcription factors were involved in PRR regulation, we treated Neuro-2A cells with ANG II with or without CREB (cAMP response element-binding protein) or AP-1 (activator protein-1) inhibitors, or CREB siRNA. CREB and AP-1 inhibitors, as well as CREB knockdown abolished ANG II-induced increases in PRR levels. ANG II also induced PRR upregulation in primary cultured neurons. Chromatin immunoprecipitation assays revealed that ANG II treatment increased CREB binding to the endogenous PRR promoter in both cultured neurons and hypothalamic tissues of DOCA-salt hypertensive mice. This increase in CREB activity was reversed by AT1R blockade. Collectively, these findings indicate that ANG II acts via AT1R to upregulate PRR expression both in cultured cells and in DOCA-salt hypertensive mice by increasing CREB binding to the PRR promoter.
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Li, Pengwei, and Mingxian Chang. "Roles of PRR-Mediated Signaling Pathways in the Regulation of Oxidative Stress and Inflammatory Diseases." International Journal of Molecular Sciences 22, no. 14 (July 19, 2021): 7688. http://dx.doi.org/10.3390/ijms22147688.
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Oxidative stress is a major contributor to the pathogenesis of various inflammatory diseases. Accumulating evidence has shown that oxidative stress is characterized by the overproduction of reactive oxygen species (ROS). Previous reviews have highlighted inflammatory signaling pathways, biomarkers, molecular targets, and pathogenetic functions mediated by oxidative stress in various diseases. The inflammatory signaling cascades are initiated through the recognition of host cell-derived damage associated molecular patterns (DAMPs) and microorganism-derived pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). In this review, the effects of PRRs from the Toll-like (TLRs), the retinoic acid-induced gene I (RIG-I)-like receptors (RLRs) and the NOD-like (NLRs) families, and the activation of these signaling pathways in regulating the production of ROS and/or oxidative stress are summarized. Furthermore, important directions for future studies, especially for pathogen-induced signaling pathways through oxidative stress are also reviewed. The present review will highlight potential therapeutic strategies relevant to inflammatory diseases based on the correlations between ROS regulation and PRRs-mediated signaling pathways.
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Li, Caixia, and Helmy M. Siragy. "Autophagy upregulates (pro)renin receptor expression via reduction of P62/SQSTM1 and activation of ERK1/2 signaling pathway in podocytes." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 313, no. 1 (July 1, 2017): R58—R64. http://dx.doi.org/10.1152/ajpregu.00088.2017.
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Autophagy plays a major role in podocytes health and disease. P62, also known as sequestosome-1 (SQSTM1), is a marker for autophagic activity and is required for the formation and degradation of ubiquitnated protein by autophagy. Knockout of p62 enhanced extracellular signal-regulated kinases (ERK1/2) activity. (pro)renin receptor (PRR) is expressed in podocytes where it contributes to the homeostasis of these cells. The influence of autophagy on PRR expression is unknown. We hypothesized that in podocytes, upregulation of autophagic activity increases PRR expression via reduction of p62 and stimulation of ERK1/2 signaling pathway. Cultured mouse podocytes were treated with the autophagy activators, rapamycin or Earle’s balanced salt solution (EBSS), for 48 h. Both rapamycin and EBSS significantly decreased p62 protein levels, increased ERK1/2 activation by phosphorylating pTpY185/187, and increased mRNA and protein expressions of PRR. Utilizing confocal microscopy demonstrated that rapamycin and EBSS significantly decreased p62/SQSTM1 and increased PRR protein expressions. Similarly, by enhancing autophagic activity by transfection with autophagy-related 5 (ATG5) cDNA or ATG7 cDNA, results similar to those observed with rapamycin and EBSS treatments were produced. Inhibition of autophagic flux with bafilomycin A1 reversed the effects of rapamycin. ERK1/2 inhibitor U0126 significantly attenuated mRNA and protein expressions of PRR in podocytes treated with rapamycin. In conclusion, upregulation of autophagy enhanced PRR expression through reduction of p62 and stimulation of ERK1/2 activity signaling pathway.
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Quadri, Syed, and Helmy M. Siragy. "Regulation of (pro)renin receptor expression in mIMCD via the GSK-3β-NFAT5-SIRT-1 signaling pathway." American Journal of Physiology-Renal Physiology 307, no. 5 (September 1, 2014): F593—F600. http://dx.doi.org/10.1152/ajprenal.00245.2014.
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The localization and regulation of (pro)renin receptor (PRR) expression in kidney collecting duct cells are not well established. We hypothesized that low salt (LS) contributes to the regulation of PRR expression in these cells via the GSK-3β-NFAT5-sirtuin1 (SIRT-1) signaling pathway. Mouse inner medullary collecting duct (mIMCD) cells were treated with NaCl at 130 (normal salt; NS), 63 (LS), or 209 mM (high salt; HS) alone or in combination with NFAT5 scrambled small interfering (si) RNA, NFAT5 siRNA, or the SIRT-1 inhibitor EX-527. Compared with NS, LS increased the mRNA and protein expression of PRR by 71% and 69% ( P < 0.05), and reduced phosphorylation of GSK-3β by 62% ( P < 0.01), mRNA and protein expressions of NFAT5 by 65% and 45% ( P < 0.05), and SIRT-1 by 44% and 50% ( P < 0.01), respectively. LS also enhanced p65 NF-κB by 102% ( P < 0.01). Treatment with HS significantly reduced the mRNA and protein expression of PRR by 32% and 23% ( P < 0.05), and increased the mRNA and protein expression of NFAT5 by 39% and 45% ( P < 0.05) and SIRT-1 by 51% and 56% ( P < 0.05), respectively. HS+NFAT5 siRNA reduced the mRNA and protein expression of NFAT5 by 51% and 35% ( P < 0.01) and increased the mRNA and protein expression of PRR by 148% and 70% ( P < 0.01), respectively. HS+EX-527 significantly increased the mRNA and protein expression of PRR by 96% and 58% ( P < 0.05), respectively. We conclude that expression of PRR in mIMCD cells is regulated by the GSK-3β-NFAT5- SIRT-1 signaling pathway.
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Heiniö, Camilla, Riikka Havunen, Joao Santos, Klaas de Lint, Victor Cervera-Carrascon, Anna Kanerva, and Akseli Hemminki. "TNFa and IL2 Encoding Oncolytic Adenovirus Activates Pathogen and Danger-Associated Immunological Signaling." Cells 9, no. 4 (March 26, 2020): 798. http://dx.doi.org/10.3390/cells9040798.
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In order to break tumor resistance towards traditional treatments, we investigate the response of tumor and immune cells to a novel, cytokine-armed oncolytic adenovirus: Ad5/3-d24-E2F-hTNFa-IRES-hIL2 (also known as TILT-123 and OAd.TNFa-IL2). There are several pattern recognition receptors (PRR) that might mediate adenovirus-infection recognition. However, the role and specific effects of each PRR on the tumor microenvironment and treatment outcome remain unclear. Hence, the aim of this study was to investigate the effects of OAd.TNFa-IL2 infection on PRR-mediated danger- and pathogen-associated molecular pattern (DAMP and PAMP, respectively) signaling. In addition, we wanted to see which PRRs mediate an antitumor response and are therefore relevant for optimizing this virotherapy. We determined that OAd.TNFa-IL2 induced DAMP and PAMP release and consequent tumor microenvironment modulation. We show that the AIM2 inflammasome is activated during OAd.TNFa-IL2 virotherapy, thus creating an immunostimulatory antitumor microenvironment.
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Ranjan, Kishu, Matija Hedl, and Clara Abraham. "The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes." Proceedings of the National Academy of Sciences 118, no. 32 (August 5, 2021): e2013500118. http://dx.doi.org/10.1073/pnas.2013500118.
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Balancing microbial-induced cytokines and microbial clearance is critical at mucosal sites such as the intestine. How the inflammatory bowel disease (IBD)–associated gene RNF186 regulates this balance is unclear. We found that macrophages from IBD-risk rs6426833 carriers in the RNF186 region showed reduced cytokines to stimulation through multiple pattern recognition receptors (PRRs). Upon stimulation of PRRs, the E3-ubiquitin ligase RNF186 promoted ubiquitination of signaling complex molecules shared across PRRs and those unique to select PRRs. Furthermore, RNF186 was required for PRR-initiated signaling complex assembly and downstream signaling. RNF186, along with its intact E3-ubiquitin ligase activity, was required for optimal PRR-induced antimicrobial reactive oxygen species, reactive nitrogen species, and autophagy pathways and intracellular bacterial clearance in human macrophages and for bacterial clearance in intestinal myeloid cells. Cells transfected with the rare RNF186-A64T IBD-risk variant and macrophages from common rs6426833 RNF186 IBD-risk carriers demonstrated a reduction in these RNF186-dependent outcomes. These studies identify mechanisms through which RNF186 regulates innate immunity and show that RNF186 IBD-risk variants demonstrate a loss of function in PRR-initiated outcomes.
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Li, Caixia, and Helmy M. Siragy. "(Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose." American Journal of Physiology-Endocrinology and Metabolism 309, no. 3 (August 1, 2015): E302—E310. http://dx.doi.org/10.1152/ajpendo.00603.2014.
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High glucose reduces autophagy and enhances apoptosis of podocytes. Previously, we reported that high glucose induced podocyte injury through upregulation of the (pro)renin receptor (PRR). We hypothesized that increasing PRR reduces autophagy and increases apoptosis of mouse podocytes exposed to high glucose via activation of the PI3K/Akt/mTOR signaling pathway. Mouse podocytes were cultured in normal (5 mmol/l) or high (25 mmol/l) d-glucose for 48 h. High glucose significantly increased mRNA and protein levels of PRR, phosphorylation of PI3K/Akt/mTOR, and p62. In contrast, high glucose decreased activation of UNC-51-like kinase-1 (ULK1) by phosphorylating Ser757 and protein levels of microtubule-associated protein-1 light chain 3B (LC3B)-II and Lamp-2. Bafilomycin A1 increased LC3BII and p62 accumulation in high-glucose-treated cells. High glucose reduced the autophagic flux. Confocal microscopy studies showed significant reduction in the protein level of LC3B in response to high glucose. Cyto-ID autophagy staining showed a significant decrease in autophagosome formation with high glucose. In the absence of PRR, activation of Akt with sc-79 or mTOR with MHY-1485 increased p62 accumulation. Caspase-3/7 activity and apoptosis monitored by TUNEL assay were significantly increased in podocytes treated with high glucose. PRR siRNA significantly reversed the effects of high glucose. Based on these data, we conclude that high glucose decreases autophagy and increases apoptosis in mouse podocytes through the PRR/PI3K/Akt/mTOR signaling pathway.
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Cheng, Shih-Chin, Louis Y. A. Chai, Leo A. B. Joosten, Anna Vecchiarelli, Bernhard Hube, Jos W. Van Der Meer, Bart Jan Kullberg, and Mihai G. Netea. "Candida albicans Releases Soluble Factors That Potentiate Cytokine Production by Human Cells through a Protease-Activated Receptor 1- and 2-Independent Pathway." Infection and Immunity 78, no. 1 (October 26, 2009): 393–99. http://dx.doi.org/10.1128/iai.01041-09.
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ABSTRACT The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRR) and transduces downstream signaling to activate the host defense. Here we report that in addition to direct PAMP-PRR interactions, live Candida albicans cells can release soluble factors to actively potentiate interleukin-6 (IL-6) and IL-8 production induced in human mononuclear cells by the fungi. Although protease-activated receptor 1 (PAR1) and PAR2 ligation can moderately upregulate Toll-like receptor 4 (TLR4)-mediated IL-8 production, no effect on the C. albicans-induced cytokine was apparent. Similarly, the blockade of PAR signaling did not reverse the potentiation of cytokine production induced by soluble factors released by C. albicans. In conclusion, C. albicans releases soluble factors that potentiate cytokine release in a PAR1/2-independent manner. Thus, human PAR1 and PAR2 have a redundant role in the activation of human cells by C. albicans.
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Hu, Ming-Ming, and Hong-Bing Shu. "Cytoplasmic Mechanisms of Recognition and Defense of Microbial Nucleic Acids." Annual Review of Cell and Developmental Biology 34, no. 1 (October 6, 2018): 357–79. http://dx.doi.org/10.1146/annurev-cellbio-100617-062903.
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Microbial nucleic acids are major signatures of invading pathogens, and their recognition by various host pattern recognition receptors (PRRs) represents the first step toward an efficient innate immune response to clear the pathogens. The nucleic acid–sensing PRRs are localized at the plasma membrane, the cytosol, and/or various cellular organelles. Sensing of nucleic acids and signaling by PRRs involve recruitment of distinct signaling components, and PRRs are intensively regulated by cellular organelle trafficking. PRR-mediated innate immune responses are also heavily regulated by posttranslational modifications, including phosphorylation, polyubiquitination, sumoylation, and glutamylation. In this review, we focus on our current understanding of recognition of microbial nucleic acid by PRRs, particularly on their regulation by organelle trafficking and posttranslational modifications. We also discuss how sensing of self nucleic acids and dysregulation of PRR-mediated signaling lead to serious human diseases.
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Gilfoy, Felicia D., and Peter W. Mason. "West Nile Virus-Induced Interferon Production Is Mediated by the Double-Stranded RNA-Dependent Protein Kinase PKR." Journal of Virology 81, no. 20 (August 8, 2007): 11148–58. http://dx.doi.org/10.1128/jvi.00446-07.
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ABSTRACT Cells carry a variety of molecules, referred to as pathogen recognition receptors (PRRs), which are able to sense invading pathogens. Interaction of PRRs with viral compounds instigates a signaling pathway(s), resulting in the activation of genes, including those for type I interferon (IFN), which are critical for an effective antiviral response. Here we demonstrate that the double-stranded RNA (dsRNA)-dependent protein kinase PKR, which has been shown to function as a PRR in cells treated with the dsRNA mimetic poly(I:C), serves as a PRR in West Nile virus (WNV)-infected cells. Evidence for PKR's role as a PRR was obtained from both human and murine cells. Using mouse embryonic fibroblasts (MEFs), we demonstrated that PKR gene knockout, posttranscriptional gene silencing of PKR mRNA using small interfering RNA (siRNA), and chemical inhibition of PKR function all interfered with IFN synthesis following WNV infection. In three different human cell lines, siRNA knockdown and chemical inhibition of PKR blocked WNV-induced IFN synthesis. Using the same approaches, we demonstrated that PKR was not necessary for Sendai virus-induced IFN synthesis, suggesting that PKR is particularly important for recognition of WNV infection. Taken together, our data suggest that PKR could serve as a PRR for recognition of WNV infection.
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Arthur, Gertrude, Jeffrey L. Osborn, and Frédérique B. Yiannikouris. "(Pro)renin receptor in the kidney: function and significance." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 320, no. 4 (April 1, 2021): R377—R383. http://dx.doi.org/10.1152/ajpregu.00259.2020.
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(Pro)renin receptor (PRR), a 350-amino acid receptor initially thought of as a receptor for the binding of renin and prorenin, is multifunctional. In addition to its role in the renin-angiotensin system (RAS), PRR transduces several intracellular signaling molecules and is a component of the vacuolar H+-ATPase that participates in autophagy. PRR is found in the kidney and particularly in great abundance in the cortical collecting duct. In the kidney, PRR participates in water and salt balance, acid-base balance, and autophagy and plays a role in development and progression of hypertension, diabetic retinopathy, and kidney fibrosis. This review highlights the role of PRR in the development and function of the kidney, namely, the macula densa, podocyte, proximal and distal convoluted tubule, and the principal cells of the collecting duct, and focuses on PRR function in body fluid volume homeostasis, blood pressure regulation, and acid-base balance. This review also explores new advances in the molecular mechanism involving PRR in normal renal health and pathophysiological states.
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Matavelli, Luis C., Jiqian Huang, and Helmy M. Siragy. "In vivo regulation of renal expression of (pro)renin receptor by a low-sodium diet." American Journal of Physiology-Renal Physiology 303, no. 12 (December 15, 2012): F1652—F1657. http://dx.doi.org/10.1152/ajprenal.00204.2012.
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Effects of low salt (LS) on (pro)renin receptor (PRR) expression are not well established. We hypothesized that LS enhances renal PRR expression via the cGMP-protein kinase G (PKG) signaling pathway. Sprague-Dawley rats were fed a normal-salt (NS) or LS diet associated with intrarenal cortical administration of vehicle (V), the nitric oxide (NO) synthase inhibitor nitro-l-arginine methyl ester (l-NAME), the NO donor S-nitroso- N-acetyl-dl-penicillamine (SNAP), the cGMP analog 8-bromoguanosine (8-Br)-cGMP, the guanylyl cyclase inhibitor 1H-[1, 2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), or a PKG inhibitor (PKGi) for 6 days via osmotic minipump. We evaluated the effects of each treatment on renal interstitial fluid (RIF) levels of nitrate/nitrite and cGMP and renal PRR expression. There were no significant changes in blood pressure with any of the treatments. Urinary sodium excretion was significantly lower in rats given a LS diet. Compared with NS + V, RIF nitrate/nitrite and cGMP levels increased in LS + V rats. In NS groups, RIF nitrate/nitrite and cGMP levels did not change with l-NAME, ODQ, or PKGi and increased in response to SNAP. 8-Br-cGMP increased RIF cGMP but not RIF nitrate/nitrite. In LS groups, RIF nitrate/nitrite decreased with l-NAME and did not change with ODQ or PKGi whereas RIF cGMP decreased with l-NAME, ODQ, and PKGi. PRR mRNA and protein increased in LS + V. In NS rats, PRR mRNA and protein increased in response to 8-Br-GMP and were not affected by any of other treatments. In LS rats, PRR mRNA and protein decreased significantly in response to l-NAME, ODQ, and PKGi. We conclude that LS intake enhances renal expression of PRR via cGMP-PKG signaling pathway.
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Jin, Zheng, and Zhenhua Zhu. "The role of TRIM proteins in PRR signaling pathways and immune-related diseases." International Immunopharmacology 98 (September 2021): 107813. http://dx.doi.org/10.1016/j.intimp.2021.107813.
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Ramkumar, Nirupama, Deborah Stuart, Elena Mironova, Vladislav Bugay, Shuping Wang, Nikita Abraham, Atsuhiro Ichihara, James D. Stockand, and Donald E. Kohan. "Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport." American Journal of Physiology-Renal Physiology 311, no. 1 (July 1, 2016): F186—F194. http://dx.doi.org/10.1152/ajprenal.00088.2016.
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The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na+ excretion and investigated the signaling mechanisms by which PRR regulates Na+ balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na+ diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na+ balance with normal- and low-Na+ intake. PRR KO mice had an attenuated hypertensive response and reduced Na+ retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na+ channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na+ wasting and reduces the hypertensive response to ANG II.
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Ng, Dennis, Leslie Summers deLuca, Yunfei Gao, Michael Wortzman, Tania Watts, and Jennifer Gommerman. "LTβR signaling in Dendritic Cells induces a Type I IFN response that is required for optimal clonal expansion of CD8+ T cells (100.40)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 100.40. http://dx.doi.org/10.4049/jimmunol.186.supp.100.40.
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Abstract During an acute infection, dendritic cells (DC) are triggered by pattern recognition receptors (PRR) to produce inflammatory molecules that are important for the expansion and function of CD8+ T lymphocytes in order to clear the infection. In contrast, tumours or autoimmune responses against tissue antigens produce very little inflammation, yet the immune response can proceed in the absence of obvious PRR activation. In these situations, DC require CD4+ T cell help to initiate CD8+ T cell-mediated immunity. Here we generated mixed chimeric mice lacking Lymphotoxin-β receptor (LTβR) specifically on the DC, and we found that they exhibit reduced CD8+ T cell expansion in a help-dependent response. In contrast, inhibition of the CD40 signaling only impaired CD8+ T cell interferon-γ (IFN-γ) production. Furthermore, we have identified that LTβR signaling in DC triggers IFN-α/β expression in the absence of any PRR ligand and is critical for antigen specific CD8+ T cell expansion. Therefore, this study demonstrates that different TNF family members provide integrative signals that shape the licensing potential of antigen-presenting DC.
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Hennrikus, Matthew, Alexis A. Gonzalez, and Minolfa C. Prieto. "The prorenin receptor in the cardiovascular system and beyond." American Journal of Physiology-Heart and Circulatory Physiology 314, no. 2 (February 1, 2018): H139—H145. http://dx.doi.org/10.1152/ajpheart.00373.2017.
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Since the prorenin receptor (PRR) was first reported, its physiological role in many cellular processes has been under intense scrutiny. The PRR is currently recognized as a multifunctional receptor with major roles as an accessory protein of the vacuolar-type H+-ATPase and as an intermediary in the Wnt signaling pathway. As a member of the renin-angiotensin system (RAS), the PRR has demonstrated to be of relevance in cardiovascular diseases (CVD) because it can activate prorenin and enhance the enzymatic activity of renin, thus promoting angiotensin II formation. Indeed, there is an association between PRR gene polymorphisms and CVD. Independent of angiotensin II, the activation of the PRR further stimulates intracellular signals linked to fibrosis. Studies using tissues and cells from a variety of organs and systems have supported its roles in multiple functions, although some remain controversial. In the brain, the PRR appears to be involved in the central regulation of blood pressure via activation of RAS- and non-RAS-dependent mechanisms. In the heart, the PRR promotes atrial structural and electrical remodeling. Nonetheless, animals overexpressing the PRR do not exhibit cardiac injury. In the kidney, the PRR is involved in the development of ureteric bud branching, urine concentration, and regulation of blood pressure. There is great interest in the PRR contributions to T cell homeostasis and to the development of visceral and brown fat. In this mini-review, we discuss the evidence for the pathophysiological roles of the PRR with emphasis in CVD.
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Bellin, Diana, Shuta Asai, Massimo Delledonne, and Hirofumi Yoshioka. "Nitric Oxide as a Mediator for Defense Responses." Molecular Plant-Microbe Interactions® 26, no. 3 (March 2013): 271–77. http://dx.doi.org/10.1094/mpmi-09-12-0214-cr.
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Sequential recognition of invading microbes and rapid induction of plant immune responses comprise at least two recognition systems. Early basal defenses are initiated by pathogen-associated molecular patterns and pattern recognition receptors (PRR) in the plasma membrane. Pathogens produce effectors to suppress defense but plants, in turn, can sense such effectors by dominant plant resistance (R) gene products. Plant PRR and R proteins modulate signaling networks for defense responses that rely on rapid production of reactive nitrogen species (RNS) and reactive oxygen species (ROS). Recent research has shown that nitric oxide (NO) mainly mediates biological function through chemical reactions between locally controlled accumulation of RNS and proteins leading to potential alteration of protein function. Many proteins specifically regulated by NO and participating in signaling during plant defense response have been identified, highlighting the physiological relevance of these modifications in plant immunity. ROS function independently or in cooperation with NO during defense, modulating the RNS signaling functions through the entire process. This review provides an overview of current knowledge about regulatory mechanisms for NO burst and signaling, and crosstalk with ROS in response to pathogen attack.
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Morales, Abigail. "DNA damage responses modulate macrophage transcriptional networks during microbial infection." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 226.29. http://dx.doi.org/10.4049/jimmunol.204.supp.226.29.
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Abstract In response to inflammatory stimuli, macrophages integrate myriad signaling pathways that influence the overall response to the pathogenic threat. Specifically, signals emanating from pattern recognition receptors (PRRs) activate several transcriptional networks that promote the expression of inflammatory mediators. Among the transcription factors activated downstream of PRR engagement is NF-κB, which promotes the production of pro-inflammatory cytokines and chemokines. Previous work has established that NF-κB is also activated downstream of DNA damage. In contrast to NF-κB activation following PRR engagement, this DNA damage-elicited signaling cascade originates in the nucleus and depends, in part, on Serine 85 phosphorylation of IKK regulatory subunit NEMO. During infection, macrophages produce genotoxic intermediates that are highly microbicidal. Recent work demonstrated that in macrophages, these agents damage macrophage DNA. We hypothesize that this DNA damage may modulate NF-κB activation downstream of PRR engagement. Indeed, we find that in activated macrophages, NEMO is phosphorylated at Serine 85, suggesting DNA damage-elicited NF-κB activation. Though previous reports have established that ATM is the kinase responsible for this signaling event, our data suggests that in macrophages, optimal NEMO S85 phosphorylation depends on the related DNA damage response kinase DNA-PKcs. Indeed, in the absence of functional DNA-PKcs, inflammatory cytokine production is markedly reduced in macrophages after exposure to bacterial stimuli. These findings underscore a previously underappreciated role for DNA-PKcs in modulating macrophage transcriptional networks during innate immune responses to infection.
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Chang, Sandra, Martin Chang, and Jourdan Posner. "Development of pattern recognition receptor ligands as malaria vaccine adjuvants (P4532)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 178.22. http://dx.doi.org/10.4049/jimmunol.190.supp.178.22.
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Abstract A critical obstacle to malaria vaccine development is the lack of appropriate adjuvants to elicit potent and protective immunity. Recent insights into the role of pattern recognition receptors (PRRs) in dendritic cell (DC) activation and identification of follicular helper T (Tfh) cells, as specialized providers of B cell help, enable a novel approach to adjuvant selection. We hypothesize that specific combinations of PRR agonists will be effective adjuvants by promoting the differentiation of Tfh cells. We evaluated PRR ligands that activate through distinct intracellular signaling pathways: a Toll-like receptor (TLR) agonist signaling through the MyD88-dependent pathway (R848), TLR agonists signaling through the TRIF-dependent pathway (p(I:C) and GLA); an agonist of Nod1 (C12-iE-DAP) that signals through RIP2; and an agonist for Mincle (synthetic trehalose-dibehenate) that signals through FcRγ Src-family kinase. R848 was a strong inducer of DC activation in vitro, particularly when combined with p(I:C), inducing significantly higher cytokine RNA (IL-12, TNFα) and protein (IL-12, TNFα, IL-6, IFN-γ), producing higher DC expression of CD86, and activating both pDCs and cDCs. IL-6, a potent Tfh stimulator, was maximal in DC cultures stimulated with R848 combinations. Ongoing studies will evaluate the ability of specific PRR combinations to polarize naïve CD4+ T cells to differentiate into Tfh cells in vitro and in vivo and provide help for P. falciparum blood-stage vaccines.
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Wang, Fei, Renfei Luo, Kexin Peng, Xiyang Liu, Chuanming Xu, Xiaohan Lu, Sunhapas Soodvilai, and Tianxin Yang. "Soluble (pro)renin receptor regulation of ENaC involved in aldosterone signaling in cultured collecting duct cells." American Journal of Physiology-Renal Physiology 318, no. 3 (March 1, 2020): F817—F825. http://dx.doi.org/10.1152/ajprenal.00436.2019.
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We have previously shown that activation of (pro)renin receptor (PRR) induces epithelial Na+ channel (ENaC) activity in cultured collecting duct cells. Here, we examined the role of soluble PRR (sPRR), the cleavage product of PRR in ENaC regulation, and further tested its relevance to aldosterone signaling. In cultured mpkCCD cells, administration of recombinant histidine-tagged sPRR (sPRR-His) at 10 nM within minutes induced a significant and transient increase in the amiloride-sensitive short-circuit current as assessed using the Ussing chamber technique. The acute ENaC activation was blocked by the NADPH oxidase 1/4 inhibitor GKT137892 and siRNA against Nox4 but not the β-catenin inhibitor ICG-001. In primary rat inner medullary collecting duct cells, administration of sPRR-His at 10 nM for 24 h induced protein expression of the α-subunit but not β- or γ-subunits of ENaC, in parallel with upregulation of mRNA expression as well as promoter activity of the α-subunit. The transcriptional activation of α-ENaC was dependent on β-catenin signaling. Consistent results obtained by epithelial volt ohmmeter measurement of equivalent current and Ussing chamber determination of short-circuit current showed that aldosterone-induced transepithelial Na+ transport was inhibited by the PRR decoy inhibitor PRO20 and PF-429242, an inhibitor of sPRR-generating enzyme site-1 protease, and the response was restored by the addition of sPRR-His. Medium sPRR was elevated by aldosterone and inhibited by PF-429242. Taken together, these results demonstrate that sPRR induces two phases of ENaC activation via distinct mechanisms and functions as a mediator of the natriferic action of aldosterone.
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Riquier-Brison, Anne D. M., Arnold Sipos, Ágnes Prókai, Sarah L. Vargas, lldikó Toma, Elliott J. Meer, Karie G. Villanueva, et al. "The macula densa prorenin receptor is essential in renin release and blood pressure control." American Journal of Physiology-Renal Physiology 315, no. 3 (September 1, 2018): F521—F534. http://dx.doi.org/10.1152/ajprenal.00029.2018.
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The prorenin receptor (PRR) was originally proposed to be a member of the renin-angiotensin system (RAS); however, recent work questioned their association. The present paper describes a functional link between the PRR and RAS in the renal juxtaglomerular apparatus (JGA), a classic anatomical site of the RAS. PRR expression was found in the sensory cells of the JGA, the macula densa (MD), and immunohistochemistry-localized PRR to the MD basolateral cell membrane in mouse, rat, and human kidneys. MD cell PRR activation led to MAP kinase ERK1/2 signaling and stimulation of PGE2 release, the classic pathway of MD-mediated renin release. Exogenous renin or prorenin added to the in vitro microperfused JGA-induced acute renin release, which was inhibited by removing the MD or by the administration of a PRR decoy peptide. To test the function of MD PRR in vivo, we established a new mouse model with inducible conditional knockout (cKO) of the PRR in MD cells based on neural nitric oxide synthase-driven Cre-lox recombination. Deletion of the MD PRR significantly reduced blood pressure and plasma renin. Challenging the RAS by low-salt diet + captopril treatment caused further significant reductions in blood pressure, renal renin, cyclooxygenase-2, and microsomal PGE synthase expression in cKO vs. wild-type mice. These results suggest that the MD PRR is essential in a novel JGA short-loop feedback mechanism, which is integrated within the classic MD mechanism to control renin synthesis and release and to maintain blood pressure.
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Ziske Maritska and Rachmat Hidayat. "The Role of Pattern Recognition Receptor (PRR) in the Body's Defense System: A Narrative Literature Review." Open Access Indonesian Journal of Medical Reviews 3, no. 2 (May 8, 2023): 394–97. http://dx.doi.org/10.37275/oaijmr.v3i2.300.
Full textAbstract:
Each cell has receptors on the cell surface that specifically bind to solutes (ligands) produced during tissue damage or infection. This review aimed to describe the role of PRR in the human body's defense system. The binding of the ligand to its receptor results in the activation of intracellular signaling pathways and cell activation. The B and T lymphocytes of the adaptive immune system have developed surface receptors (that is, the T-cell receptor, or TCR, and the B-cell receptor, or BCR) that bind a broad spectrum of antigens. The cells involved in innate resistance have developed a distinct set of receptors that recognize a much more limited array of specific molecules. These are called pattern recognition receptor (PRR), and they recognize the molecular patterns in infectious agents or their products (pathogen-associated molecular patterns, or PAMP) or products of cellular damage (necrosis or apoptosis; molecular pattern-associated damage, or DAMPs). In conclusion, the pattern recognition receptor (PRR) is a receptor complex that interacts with various molecules, such as PAMP and DAMPs. PRR bonds with these various molecules and play a role in various actions of innate immunity and adaptive immunity.
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Xiong, Lei, Ji-Ung Jung, Hao-Han Guo, Jin-Xiu Pan, Xiang-Dong Sun, Lin Mei, and Wen-Cheng Xiong. "Osteoblastic Lrp4 promotes osteoclastogenesis by regulating ATP release and adenosine-A2AR signaling." Journal of Cell Biology 216, no. 3 (February 13, 2017): 761–78. http://dx.doi.org/10.1083/jcb.201608002.
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Bone homeostasis depends on the functional balance of osteoblasts (OBs) and osteoclasts (OCs). Lrp4 is a transmembrane protein that is mutated in patients with high bone mass. Loss of Lrp4 in OB-lineage cells increases bone mass by elevating bone formation by OBs and reducing bone resorption by OCs. However, it is unclear how Lrp4 deficiency in OBs impairs osteoclastogenesis. Here, we provide evidence that loss of Lrp4 in the OB lineage stabilizes the prorenin receptor (PRR) and increases PRR/V-ATPase–driven ATP release, thereby enhancing the production of the ATP derivative adenosine. Both pharmacological and genetic inhibition of adenosine-2A receptor (A2AR) in culture and Lrp4 mutant mice diminishes the osteoclastogenic deficit and reduces trabecular bone mass. Furthermore, elevated adenosine-A2AR signaling reduces receptor activator of nuclear factor κB (RANK)–mediated osteoclastogenesis. Collectively, these results identify a mechanism by which osteoblastic Lrp4 controls osteoclastogenesis, reveal a cross talk between A2AR and RANK signaling in osteoclastogenesis, and uncover an unrecognized pathophysiological mechanism of high-bone-mass disorders.
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Yu, Huibin, Ryan C. Bruneau, Greg Brennan, and Stefan Rothenburg. "Battle Royale: Innate Recognition of Poxviruses and Viral Immune Evasion." Biomedicines 9, no. 7 (July 1, 2021): 765. http://dx.doi.org/10.3390/biomedicines9070765.
Full textAbstract:
Host pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs), which are molecular signatures shared by different pathogens. Recognition of PAMPs by PRRs initiate innate immune responses via diverse signaling pathways. Over recent decades, advances in our knowledge of innate immune sensing have enhanced our understanding of the host immune response to poxviruses. Multiple PRR families have been implicated in poxvirus detection, mediating the initiation of signaling cascades, activation of transcription factors, and, ultimately, the expression of antiviral effectors. To counteract the host immune defense, poxviruses have evolved a variety of immunomodulators that have diverse strategies to disrupt or circumvent host antiviral responses triggered by PRRs. These interactions influence the outcomes of poxvirus infections. This review focuses on our current knowledge of the roles of PRRs in the recognition of poxviruses, their elicited antiviral effector functions, and how poxviral immunomodulators antagonize PRR-mediated host immune responses.
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Doehle, Brian P., Kristina Chang, Arjun Rustagi, John McNevin, M. Juliana McElrath, and Michael Gale. "Vpu Mediates Depletion of Interferon Regulatory Factor 3 during HIV Infection by a Lysosome-Dependent Mechanism." Journal of Virology 86, no. 16 (May 16, 2012): 8367–74. http://dx.doi.org/10.1128/jvi.00423-12.
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HIV has evolved sophisticated mechanisms to avoid restriction by intracellular innate immune defenses that otherwise serve to control acute viral infection and virus dissemination. Innate defenses are triggered when pattern recognition receptor (PRR) proteins of the host cell engage pathogen-associated molecule patterns (PAMPs) present in viral products. Interferon regulatory factor 3 (IRF3) plays a central role in PRR signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Productive infection of T cells by HIV is dependent upon the targeted proteolysis of IRF3 that occurs through a virus-directed mechanism that results in suppression of innate immune defenses. However, the mechanisms by which HIV controls innate immune signaling and IRF3 function are not defined. Here, we examined the innate immune response induced by HIV strains identified through their differential control of PRR signaling. We identified viruses that, unlike typical circulating HIV strains, lack the ability to degrade IRF3. Our studies show that IRF3 regulation maps specifically to the HIV accessory protein Vpu. We define a molecular interaction between Vpu and IRF3 that redirects IRF3 to the endolysosome for proteolytic degradation, thus allowing HIV to avoid the innate antiviral immune response. Our studies reveal that Vpu is an important IRF3 regulator that supports acute HIV infection through innate immune suppression. These observations define the Vpu-IRF3 interface as a novel target for therapeutic strategies aimed at enhancing the immune response to HIV.
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Liang, Keke, Evan R. Abt, Thuc M. Le, Arthur Cho, Amanda M. Dann, Jing Cui, Luyi Li, et al. "STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging." Proceedings of the National Academy of Sciences 118, no. 36 (September 3, 2021): e2105390118. http://dx.doi.org/10.1073/pnas.2105390118.
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Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling–induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling–dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist–based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.
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Huang, Jiqian, and Helmy M. Siragy. "Glucose Promotes the Production of Interleukine-1β and Cyclooxygenase-2 in Mesangial Cells via Enhanced (Pro)Renin Receptor Expression." Endocrinology 150, no. 12 (October 27, 2009): 5557–65. http://dx.doi.org/10.1210/en.2009-0442.
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Abstract (Pro)renin receptor (PRR) is present in renal glomeruli, and its expression is up-regulated in diabetes. Similarly, renal inflammation is increased in the presence of hyperglycemia. The linkage between PRR and renal inflammation is not well established. We hypothesized that glucose-induced up-regulation of PRR leads to increased production of the proinflammatory factors IL-1β and cyclooxygenase-2 (COX-2). Studies were conducted in rat mesangial cells (RMCs) exposed to 30 mmd-glucose for 2 wk followed by PRR small interfering RNA knockdown, IL-1 receptor blockade with IL-1 receptor antagonist or angiotensin II type 1 receptor blockade with valsartan. The results showed that d-glucose treatment up-regulates prorenin, renin, angiotensin II, PRR, IL-1β, and COX-2 mRNA and protein expression and increases phosphorylation of ERK1/2, c-Jun N-terminal kinase, c-Jun, and nuclear factor-κB (NF-κB) p65 (serine 276,468 and 536), respectively. PRR small interfering RNA attenuated PRR, IL-1β, and COX-2 mRNA and protein expressions and significantly decreased angiotensin II production and phosphorylation of ERK1/2 and NF-κB p65 associated with high glucose exposure. Similarly, IL-1 receptor antagonist significantly reduced COX-2 mRNA and protein expression induced by high glucose. COX-2 inhibition reduced high-glucose-induced PRR expression. We conclude that glucose induces the up-regulation of PRR and its ligands prorenin and renin, leading to increased IL-1β and COX-2 production via the angiotensin II-dependent pathway. It is also possible that PRR could enhance the production of these inflammatory cytokines through direct stimulation of ERK1/2-NF-κB signaling cascade.
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Ravichandran, Aarthi, and Boon Chuan Low. "SmgGDS antagonizes BPGAP1-induced Ras/ERK activation and neuritogenesis in PC12 cell differentiation." Molecular Biology of the Cell 24, no. 2 (January 15, 2013): 145–56. http://dx.doi.org/10.1091/mbc.e12-04-0300.
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BPGAP1 is a Rho GTPase-activating protein (RhoGAP) that regulates cell morphogenesis, cell migration, and ERK signaling by the concerted action of its proline-rich region (PRR), RhoGAP domain, and the BNIP-2 and Cdc42GAP homology (BCH) domain. Although multiple cellular targets for the PRR and RhoGAP have been identified, and their functions delineated, the mechanism by which the BCH domain regulates functions of BPGAP1 remains unclear. Here we show that its BCH domain induced robust ERK activation leading to PC12 cell differentiation by targeting specifically to K-Ras. Such stimulatory effect was inhibited, however, by both dominant-negative mutants of Mek2 (Mek2-K101A) and K-Ras (K-Ras-S17N) and also by the small G-protein GDP dissociation stimulator (SmgGDS). Consequently SmgGDS knockdown released this inhibition and resulted in a superinduction of K-Ras activation and PC12 differentiation mediated by BCH domain. These results demonstrate the versatility of the BCH domain of BPGAP1 in regulating ERK signaling by involving K-Ras and SmgGDS and support the unique role of BPGAP1 as a dual regulator for Ras and Rho signaling in cell morphogenesis and differentiation.
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Chang, Hung-Chih, Jean Lu, and Hui-Chen Chen. "TRIM37 regulates allergic airway inflammation in a murine model of asthma." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 44.34. http://dx.doi.org/10.4049/jimmunol.200.supp.44.34.
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Abstract Patients with asthma, an allergic airway inflammation disease caused by dysregulation of T helper cell type 2 (TH2), have dramatically increased in the past decades and cost of care is more than 11.3 billion per year. Evidence reveal that activation of pattern recognition receptor (PRR) signaling in both hematopoietic and non-hematopoietic compartment are critical for the development of allergic airway inflammation. TRIM37 is the only member of Tripartite motif (TRIM) family protein that contains TRAF domain, studies indicated that TRIM37 might involve in regulating PRR-, TNFR- and cytokine-mediated signaling pathways suggesting its important role in regulating immune responses. However, whether there is functional impact of TRIM37 on the development of asthma remains to be examined. Using immunohistochemistry staining of lung tissues from naïve and allergen-induced inflamed mice, positive staining of TRIM37 was observed in airway epithelial cells. Interestingly, the expression level was further augmented when lung was inflamed. Functional analysis of TRIM37 indicated that TRIM37 was involved in regulating TLR-mediated signaling in airway epithelial cells, as production of pro-inflammatory cytokines was reduced in response to TLR agonists when TRIM37 was knocked-down in the cells. Furthermore, when TRIM37 were knocked-down by intratracheally delivering lentivirus carrying TRIM37shRNA into the sensitized mice before challenge showed that knockdown of TRIM37 expression in the lung during challenge diminished cardinal features of asthma. These findings suggested the involvement of TRIM37 in allergic airway inflammation.
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Robinson, Matthew J., Fabiola Osorio, Marcela Rosas, Rui P. Freitas, Edina Schweighoffer, Olaf Groß, J. Sjef Verbeek, et al. "Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection." Journal of Experimental Medicine 206, no. 9 (August 24, 2009): 2037–51. http://dx.doi.org/10.1084/jem.20082818.
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Innate immune cells detect pathogens via pattern recognition receptors (PRRs), which signal for initiation of immune responses to infection. Studies with Dectin-1, a PRR for fungi, have defined a novel innate signaling pathway involving Syk kinase and the adaptor CARD9, which is critical for inducing Th17 responses to fungal infection. We show that another C-type lectin, Dectin-2, also signals via Syk and CARD9, and contributes to dendritic cell (DC) activation by fungal particles. Unlike Dectin-1, Dectin-2 couples to Syk indirectly, through association with the FcRγ chain. In a model of Candida albicans infection, blockade of Dectin-2 did not affect innate immune resistance but abrogated Candida-specific T cell production of IL-17 and, in combination with the absence of Dectin-1, decreased Th1 responses to the organism. Thus, Dectin-2 constitutes a major fungal PRR that can couple to the Syk–CARD9 innate signaling pathway to activate DCs and regulate adaptive immune responses to fungal infection.
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Hanning, Charles, Jong Yu, Pamela Haile, Linda Cassillas, Kevin Foley, Peter Gough, John Bertin, and Bart Votta. "Inhibition of synergy between NOD2 & TLR signaling pathways underlies the profound efficacy of RIP2 kinase inhibitors in models of inflammatory bowel disease (INM6P.415)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 122.12. http://dx.doi.org/10.4049/jimmunol.192.supp.122.12.
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Abstract Loss of intestinal epithelial barrier integrity in inflammatory bowel disease (IBD) leads to aberrant interaction between commensal bacteria and mucosal immune cells. This triggers inflammation via activation of pattern recognition receptor (PRR) signaling pathways. Which PRR signaling complexes are critical in mediating disease pathogenesis remains to be elucidated. Our recent studies have shown that selective and potent inhibitors of RIP2 kinase, the signaling partner of NOD1 and NOD2, can dramatically reduce murine TNBS-induced colitis and the spontaneous release of proinflammatory cytokines in cultured intestinal biopsies from IBD patients. The striking magnitude of the inhibition observed led us to interrogate the effect of these inhibitors on the modulation of crosstalk between NOD1/2 and other PRRs. Using human PBMCs we defined conditions for observing synergistic cytokine release (TNF-α, IL-6) in response to combinations of NOD2 and either TLR2, TLR4, or TLR5 ligands. In each instance, selective inhibition of RIP2 kinase activity robustly blocked synergistic cytokine release, but had little or no effect on TLR ligand alone induced cytokine production. These results suggest that RIP2 kinase inhibitors are likely to have profound anti-inflammatory effects in situations where multiple PRRs are being stimulated simultaneously, and illustrate the potential of RIP2 inhibitors as therapeutics for the treatment of human inflammatory diseases.