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1
De Martinis, Massimo, Lia Ginaldi, Maria Maddalena Sirufo, Giovanni Pioggia, Gioacchino Calapai, Sebastiano Gangemi, and Carmen Mannucci. "Alarmins in Osteoporosis, RAGE, IL-1, and IL-33 Pathways: A Literature Review." Medicina 56, no. 3 (March 19, 2020): 138. http://dx.doi.org/10.3390/medicina56030138.
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Alarmins are endogenous mediators released by cells following insults or cell death to alert the host’s innate immune system of a situation of danger or harm. Many of these, such as high-mobility group box-1 and 2 (HMGB1, HMGB2) and S100 (calgranulin proteins), act through RAGE (receptor for advanced glycation end products), whereas the IL-1 and IL-33 cytokines bind the IL-1 receptors type I and II, and the cellular receptor ST2, respectively. The alarmin family and their signal pathways share many similarities of cellular and tissue localization, functions, and involvement in various physiological processes and inflammatory diseases including osteoporosis. The aim of the review was to evaluate the role of alarmins in osteoporosis. A bibliographic search of the published scientific literature regarding the role of alarmins in osteoporosis was organized independently by two researchers in the following scientific databases: Pubmed, Scopus, and Web of Science. The keywords used were combined as follows: “alarmins and osteoporosis”, “RAGE and osteoporosis”, “HMGB1 and osteoporosis”, “IL-1 and osteoporosis”, “IL 33 and osteopororsis”, “S100s protein and osteoporosis”. The information was summarized and organized in the present review. We highlight the emerging roles of alarmins in various bone remodeling processes involved in the onset and development of osteoporosis, as well as their potential role as biomarkers of osteoporosis severity and progression. Findings of the research suggest a potential use of alarmins as pharmacological targets in future therapeutic strategies aimed at preventing bone loss and fragility fractures induced by aging and inflammatory diseases.
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Lu, Huijiao, Mengyi Zhu, Lin Qu, Hongwei Shao, Rongxin Zhang, and Yan Li. "Oncogenic Role of HMGB1 as an Alarming in Robust Prediction of Immunotherapy Response in Colorectal Cancer." Cancers 14, no. 19 (October 5, 2022): 4875. http://dx.doi.org/10.3390/cancers14194875.
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Objective: To assess the correlation between HMGB1 expression and the patient prognosis in a multicancer context. Methods: The potential oncogenic role of HMGB1 was explored in forty tumors through the TCGA, GEO, and Oncomine datasets. We analyzed the clinical prognostic value and antitumor immunotherapy of HMGB1 in a multicancer context using GEO (GSE111636). Results: High expression of HMGB1 is present in multicancer cases, and its low expression is closely associated with the prognostic survival of patients, in terms of both overall and disease-free survival in ACC and LUAD. Further investigation revealed that the high expression of gastric and lung cancer is closely associated with low risk and better prognosis of patients based on COX and Kaplan–Meier analysis of OS, FP and PPS. HMGB1 expression was found to be significantly correlated with cancer-associated fibroblast and CD8+ T cell infiltration in the TME. The analysis of GO functional annotation/KEGG pathways indicates that HMGB1 may regulate tumor immunity-related pathways, such as the tumor immunotherapy response in colorectal cancer. The function of four genes as hubs are confirmed by in vitro HMGB1 knockdown which led to inhibition of cell proliferation and metastasis in SW620 and SW480 cells. Conclusion: HMGB1 is a potential novel biomarker for improving clinical prognosis and antitumor immunotherapy efficacy. CDK1, HMGB2, SSRP1, and H2AFV may serve as key nodes for HMGB1 in colorectal cancer.
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Palumbo, Antonino, Fabiola Atzeni, Giuseppe Murdaca, and Sebastiano Gangemi. "The Role of Alarmins in Osteoarthritis Pathogenesis: HMGB1, S100B and IL-33." International Journal of Molecular Sciences 24, no. 15 (July 29, 2023): 12143. http://dx.doi.org/10.3390/ijms241512143.
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Osteoarthritis (OA) is a multifactorial disease in which genetics, aging, obesity, and trauma are well-known risk factors. It is the most prevalent joint disease and the largest disability problem worldwide. Recent findings have described the role of damage-associated molecular patterns (DAMPs) in the course of the disease. In particular, alarmins such as HMGB1, IL-33, and S100B, appear implicated in enhancing articular inflammation and favouring a catabolic switch in OA chondrocytes. The aims of this review are to clarify the molecular signalling of these three molecules in OA pathogenesis, to identify their possible use as staging biomarkers, and, most importantly, to find out whether they could be possible therapeutic targets. Osteoarthritic cartilage expresses increased levels of all three alarmins. HMGB1, in particular, is the most studied alarmin with increased levels in cartilage, synovium, and synovial fluid of OA patients. High levels of HMGB1 in synovial fluid of OA joints are positively correlated with radiological and clinical severity. Counteracting HMGB1 strategies have revealed improving results in articular cells from OA patients and in OA animal models. Therefore, drugs against this alarmin, such as anti-HMGB1 antibodies, could be new treatment possibilities that can modify the disease course since available medications only alleviate symptoms.
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Casciaro, Marco, Eleonora Di Salvo, and Sebastiano Gangemi. "HMGB-1 in Psoriasis." Biomolecules 12, no. 1 (December 31, 2021): 60. http://dx.doi.org/10.3390/biom12010060.
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Psoriasis is a multifactorial pathology linked to systemic inflammation. Enhanced keratinocytes proliferation and a minor maturation state of the cells are typical features. Perivascular T cells, dendritic cells, macrophages, and neutrophilic granulocytes are part of the scenario completed by apoptosis dysregulation. Several proinflammatory mediators, alarmins and growth factors are increased too, both in the skin and the patients’ blood. HMGB1 is important as an alarmin in several inflammatory conditions. Released after cellular damage, HMGB1 acts as a danger signal. Several studies have considered its role in psoriasis pathogenesis. We evaluated its level in psoriasis and the potential of the alarmin blockade through standard therapies, biological treatments and using monoclonal antibodies. PV patients were shown to have significantly increased levels of HMGB1 both in lesional skin and in serum, which were linked, in some cases, to other pro-inflammatory markers and alarmins. In most cases these parameters were correlated with PASI score. Data demonstrated that blocking HMGB1 is effective in ameliorating psoriasis. Focusing on this approach could be valuable in terms of a therapeutic option for counteracting immune-related diseases in a way unthinkable until few years ago.
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Yang, De, Yuri V. Postnikov, Yana Li, Poonam Tewary, Gonzalo de la Rosa, Feng Wei, Dennis Klinman, et al. "High-mobility group nucleosome-binding protein 1 acts as an alarmin and is critical for lipopolysaccharide-induced immune responses." Journal of Experimental Medicine 209, no. 1 (December 19, 2011): 157–71. http://dx.doi.org/10.1084/jem.20101354.
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Alarmins are endogenous mediators capable of promoting the recruitment and activation of antigen-presenting cells (APCs), including dendritic cells (DCs), that can potentially alert host defense against danger signals. However, the relevance of alarmins to the induction of adaptive immune responses remains to be demonstrated. In this study, we report the identification of HMGN1 (high-mobility group nucleosome-binding protein 1) as a novel alarmin and demonstrate that it contributes to the induction of antigen-specific immune responses. HMGN1 induced DC maturation via TLR4 (Toll-like receptor 4), recruitment of APCs at sites of injection, and activation of NF-κB and multiple mitogen-activated protein kinases in DCs. HMGN1 promoted antigen-specific immune response upon co-administration with antigens, and Hmgn1−/− mice developed greatly reduced antigen-specific antibody and T cell responses when immunized with antigens in the presence of lipopolysaccharide (LPS). The impaired ability of Hmgn1−/− mice to mount antigen-specific immune responses was accompanied by both deficient DC recruitment at sites of immunization and reduced production of inflammatory cytokines. Bone marrow chimera experiments revealed that HMGN1 derived from nonleukocytes was critical for the induction of antigen-specific antibody and T cell responses. Thus, extracellular HMGN1 acts as a novel alarmin critical for LPS-induced development of innate and adaptive immune responses.
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Jiang, Lili, Yijia Shao, Yao Tian, Changsheng Ouyang, and Xiaohua Wang. "Nuclear Alarmin Cytokines in Inflammation." Journal of Immunology Research 2020 (December 4, 2020): 1–8. http://dx.doi.org/10.1155/2020/7206451.
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Pathogen-associated molecular patterns (PAMPs) are some nonspecific and highly conserved molecular structures of exogenous specific microbial pathogens, whose products can be recognized by pattern recognition receptor (PRR) on innate immune cells and induce an inflammatory response. Under physiological stress, activated or damaged cells might release some endogenous proteins that can also bind to PRR and cause a harmful aseptic inflammatory response. These endogenous proteins were named damage-associated molecular patterns (DAMPs) or alarmins. Indeed, alarmins can also play a beneficial role in the tissue repair in certain environments. Besides, some alarmin cytokines have been reported to have both nuclear and extracellular effects. This group of proteins includes high-mobility group box-1 protein (HMGB1), interleukin (IL)-33, IL-1α, IL-1F7b, and IL-16. In this article, we review the involvement of nuclear alarmins such as HMGB1, IL-33, and IL-1α under physiological state or stress state and suggest a novel activity of these molecules as central initiators in the development of sterile inflammation.
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Briquet, Sylvie, Nadou Lawson-Hogban, Bertrand Boisson, Miguel P. Soares, Roger Péronet, Leanna Smith, Robert Ménard, Michel Huerre, Salah Mécheri, and Catherine Vaquero. "Disruption of Parasitehmgb2Gene Attenuates Plasmodium berghei ANKA Pathogenicity." Infection and Immunity 83, no. 7 (April 27, 2015): 2771–84. http://dx.doi.org/10.1128/iai.03129-14.
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Eukaryotic high-mobility-group-box (HMGB) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. When released into the extracellular milieu, HMGB1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. We found that thePlasmodiumgenome encodes two genuine HMGB factors,PlasmodiumHMGB1 and HMGB2, that encompass, like their human counterparts, a proinflammatory domain. Given that these proteins are released from parasitized red blood cells, we then hypothesized thatPlasmodiumHMGB might contribute to the pathogenesis of experimental cerebral malaria (ECM), a lethal neuroinflammatory syndrome that develops in C57BL/6 (susceptible) mice infected withPlasmodium bergheiANKA and that in many aspects resembles human cerebral malaria elicited byP. falciparuminfection. The pathogenesis of experimental cerebral malaria was suppressed in C57BL/6 mice infected withP. bergheiANKA lacking thehmgb2gene (Δhmgb2ANKA), an effect associated with a reduction of histological brain lesions and with lower expression levels of several proinflammatory genes. The incidence of ECM inpbhmgb2-deficient mice was restored by the administration of recombinantPbHMGB2. Protection from experimental cerebral malaria in Δhmgb2ANKA-infected mice was associated with reduced sequestration in the brain of CD4+and CD8+T cells, including CD8+granzyme B+and CD8+IFN-γ+cells, and, to some extent, neutrophils. This was consistent with a reduced parasite sequestration in the brain, lungs, and spleen, though to a lesser extent than in wild-typeP. bergheiANKA-infected mice. In summary,PlasmodiumHMGB2 acts as an alarmin that contributes to the pathogenesis of cerebral malaria.
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Yang, De, Yuri Postnikov, Yana Li, Poonam Tewary, Gonzalo de la Rosa, Dennis Kliman, Takashi Furusawa, Michael Bustin, Feng Wei, and Joost Oppenheim. "High mobility group nucleosome-binding protein 1 acts as an alarmin critical for the induction of immune response (113.7)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 113.7. http://dx.doi.org/10.4049/jimmunol.186.supp.113.7.
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Abstract Alarmins, defined as endogenous mediator(s) capable of promoting the recruitment and activation of antigen-presenting cells (APCs) including dendritic cells (DCs), can potentially promote immunity, however, their essential contribution to the induction immune responses remain to be demonstrated. Here we report the identification of HMGN1 as a novel alarmin that is critical to the induction of antigen-specific immune response. HMGN1 induced DC maturation and recruitment of APCs and activated NF-κB and multiple MAPKs, in a MyD88-dependent manner. HMGN1 promoted antigen-specific immune response upon co-administration with an antigen. Furthermore, knockout of HMGN1 in mice greatly reduced antigen-specific antibody and T cell responses upon intraperitoneal immunization with an antigen using LPS as an adjuvant. The impaired ability of HMGN1 KO mice to mount antigen-specific immune responses was accompanied by both deficient DC recruitment at sites of immunization and reduced production of inflammatory cytokines. Bone marrow chimera experiments revealed that HMGN1 derived from non-leukocytes played a more critical role in the induction of antigen-specific antibody and T cell responses. Thus, HMGN1 acts as a novel alarmin critical for the induction of adaptive immune response.
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Bidwell, Joseph P., Jieping Yang, and Alexander G. Robling. "Is HMGB1 an osteocyte alarmin?" Journal of Cellular Biochemistry 103, no. 6 (2008): 1671–80. http://dx.doi.org/10.1002/jcb.21572.
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Mezentsev, A. V., E. V. Denisova, V. V. Sobolev, and I. M. Korsunskaya. "The role of alarmins in the pathogenesis of psoriasis." Meditsinskiy sovet = Medical Council, no. 14 (September 28, 2023): 62–70. http://dx.doi.org/10.21518/ms2023-276.
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Alarmins are a group of immune activating proteins/peptides that initiate an inflammatory process by interacting with immune cells. The alarmins are biosynthesized as a result of cell injury, often due to proteolysis of native proteins. Most often, the alarmins are released into the extracellular matrix as a result of infection, burn or trauma. Several studies have been conducted recently to determine the role of alarmins in the pathogenesis of autoimmune diseases. This work was aimed to assess the clinical potential of alarmins and characterize their role in the pathogenesis of psoriasis. The proposed review analysed 6 groups of alarmins with increased expression in the skin of patients with psoriasis: defensins, CAMP/LL-37, amphoterin/HMGB1, interleukin-1 (IL-1)-like cytokine family members (IL1 and -33) with alarmin properties, heat shock proteins, and proteins of the S100 family. The presented work also discusses the therapeutic potential of alarmins: the possibility to use them as the drug therapy target, as well as to establish diagnosis and monitor the progress of psoriasis. The further experimental studies are supposed to pay considerable attention to alarmin receptors, as well as members involved in the signalling pathways they initiated. These work findings help to obtain biologically active compounds that will be able to specifically and effectively inhibit the physiological effects of alarmins, as well as control the inflammatory process they induced. It seems certain that the use of alarmin antagonists in clinical practice will prove useful in the treatment of both psoriasis and other chronic autoimmune diseases, especially in cases where the most commonly used therapies are not effective enough.
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Davalos, Albert R., Misako Kawahara, Gautam K. Malhotra, Nicholas Schaum, Jiahao Huang, Urvi Ved, Christian M. Beausejour, Jean-Philippe Coppe, Francis Rodier, and Judith Campisi. "p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes." Journal of Cell Biology 201, no. 4 (May 6, 2013): 613–29. http://dx.doi.org/10.1083/jcb.201206006.
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Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation.
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Cher, Jonathon Z. B., Moeed Akbar, Susan Kitson, Lindsay A. N. Crowe, Emma Garcia-Melchor, Stephen C. Hannah, Michael McLean, et al. "Alarmins in Frozen Shoulder: A Molecular Association Between Inflammation and Pain." American Journal of Sports Medicine 46, no. 3 (November 30, 2017): 671–78. http://dx.doi.org/10.1177/0363546517741127.
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Background: The pathophysiological mechanisms behind proliferation of fibroblasts and deposition of dense collagen matrix in idiopathic frozen shoulder remain unclear. Alarmins (also known as danger signals) are endogenous molecules that are released into the extracellular milieu after infection or tissue injury and that signal cell and tissue damage. Purpose: To investigate whether the presence of alarmins is higher in patients with idiopathic frozen shoulder than in control subjects. Study Design: Controlled laboratory study. Methods: Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients with unstable shoulders (control). The samples were stained with hematoxylin and eosin (H&E) and analyzed by immunohistochemistry using antibodies against alarmin molecules including high-mobility group protein B1 (HMGB1), interleukin 33, S100A8, S100A9, and the peripheral nerve marker PGP9.5. Immunoreactivities were rated in a blinded fashion from “none” to “strong.” Immunohistochemical distribution within the capsule was noted. Before surgery, patient-ranked pain frequency, severity, stiffness, and the range of passive shoulder motion were recorded and statistically analyzed. Results: Compared with control patients, patients with frozen shoulder had greater frequency and severity of self-reported pain ( P = .02) and more restricted range of motion in all planes ( P < .05). H&E-stained capsular tissue from frozen shoulder showed fibroblastic hypercellularity and increased subsynovial vascularity. Immunoreactivity of alarmins was significantly stronger in frozen shoulder capsules compared with control capsules ( P < .05). Furthermore, the expression of the alarmin molecule HMGB1 significantly correlated ( r > 0.9, P < .05) with the severity of patient-reported pain. Conclusion: This study demonstrates a potential role for key molecular danger signals in frozen shoulder and suggests an association between the expression of danger molecules and the pain experienced by patients.
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Yuan, Kaiqiang, Hu Wang, Yingming Zhou, and Taolang Li. "The Role of Alarmins in Breast Cancer." International Journal of Biology and Life Sciences 8, no. 1 (November 22, 2024): 31–40. http://dx.doi.org/10.54097/30f8ej75.
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Breast cancer (BC) remains the most common malignant tumor in women globally, with its incidence and mortality ranking first and second among female cancers, respectively. Despite continuous innovation and progress in modern medicine, current clinical treatment strategies for breast cancer still face high mortality rates. Therefore, developing new therapeutic targets and strategies is urgently needed. Alarmins are a class of endogenous molecules released during non-programmed cell death (such as infection or injury), and they typically serve as early warning signals for the immune system. Early research primarily focused on the role of alarmins in autoimmune and immune-mediated diseases, but recent studies have shown that alarmins also play a crucial role in the development, progression, and therapeutic response of breast cancer. In this review, we will discuss the role of alarmin family members (such as HMGB1, S100A8, S100A9, and IL-33) in breast cancer and their potential as therapeutic targets.
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Borsky, Pavel, Zdenek Fiala, Ctirad Andrys, Martin Beranek, Kvetoslava Hamakova, Andrea Malkova, Tereza Svadlakova, et al. "Alarmins HMGB1, IL-33, S100A7, and S100A12 in Psoriasis Vulgaris." Mediators of Inflammation 2020 (April 15, 2020): 1–7. http://dx.doi.org/10.1155/2020/8465083.
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Background. Psoriasis vulgaris is a chronic autoimmune disease associated with systemic inflammation. Increased levels of numerous cytokines, chemokines, growth factors, and other molecules were found in the skin and in the circulation of psoriatic patients. Alarmins, also known as danger signals, are intracellular proteins, which are released to an extracellular space after infection or damage. They are the markers of cell destructive processes. Objective. The aim of the present study was to evaluate the suitability of selected alarmins (HMGB1, IL-33, S100A7, and S100A12) as potential biomarkers of severity of psoriasis and to explore possible relationships between these proteins for the purpose of better understanding their roles in the immunopathology of psoriasis. Methods. The serum levels of selected alarmins were measured in 63 psoriatic patients and 95 control individuals. The levels were assessed by the ELISA technique using commercial kits. The data were statistically processed with MedCalc version 19.0.5. Results. In psoriatic patients, we found significantly increased levels of HMGB1 (p<0.05), IL-33 (p<0.01), S100A7 (p<0.0001), and S100A12 (p<0.0001). In addition, we found a significant relationship between HMGB1 and S100A7 (Spearman’s rho=0.276, p<0.05) in the patients and significant relationship between HMGB1 and IL-33 in the controls (Spearman’s rho=0.416, p<0.05). We did not find any relationship between observed alarmins and the disease severity. Conclusions. The alarmins HMGB1, IL-33, S100A7, and S100A12 were significantly elevated in the serum of patients, which states the hypothesis that they play specific roles in the immunopathology of psoriasis. However, we have not yet found a relationship between observed alarmins and the disease severity. The discovery of the relationship between HMGB1 and S100A7 is a novelty that should be studied in the future to further clarify its role and importance.
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Strohalmová, Sabina, Kateřina Levová, Aleš Antonín Kuběna, David Hoskovec, Zdeněk Krška, Tomáš Zima, and Marta Kalousová. "Alarmins and Related Molecules in Elective Surgery." Folia Biologica 69, no. 2 (2023): 50–58. http://dx.doi.org/10.14712/fb2023069020050.
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Surgery is associated with alterations of alarmins’ and related molecules’ levels. The aim of this study was to investigate which biomarkers are most involved in surgery. The studied group consisted of 58 patients with inguinal or umbilical hernia or cholecystolithiasis and 21 healthy controls for comparison. We also added seven acute patients with appendicitis, cholecystitis and incarcerated hernia. Serum concentrations of soluble receptor of advanced glycation end-products (sRAGE), extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE), calprotectin, high mobility group box 1 (HMGB1) and interleukin 6 (IL-6) were analysed by ELISA before and after surgery. Preoperative concentrations of calprotectin were significantly decreased while concentrations of sRAGE were significantly increased in patients compared to controls; the concentrations of EN-RAGE and HMGB1 did not differ significantly. IL-6 levels were undetectable in elective patients preoperatively and in controls. Postoperatively, there was a significant increase of EN-RAGE, calprotectin, HMGB1, and IL-6 and a significant decrease of sRAGE compared to preoperative levels. In acute patients, all tested molecules except for sRAGE were significantly increased preoperatively, and sRAGE was significantly decreased. In contrast, after surgery, we could observe a further increase in IL-6; the other biomarkers did not differ significantly. We can conclude that the concentrations of all tested biomarkers are significantly influenced by elective surgery. The postoperative levels of all tested molecules increase except for sRAGE, whose level is significantly decreased after surgery. In acute states, these molecules are already increased, and the influence of surgery is, apart from IL-6, insignificant.
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Chung, Hyunwoo, Sol Seo, Sung Ji Hong, So Won Choi, and Chung-Gyu Park. "The alarmin HMGB1 in cell cytoplasm can modulate the apoptosis to autophagy switch of pancreatic beta cells under stress." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 161.28. http://dx.doi.org/10.4049/jimmunol.204.supp.161.28.
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Abstract High mobility group box 1 (HMGB1) is an infamous alarmin which is known to be harmful to pancreatic beta cells and associated with diabetes mellitus pathogenesis and pancreatic islet graft failure. However, recent studies have indicated that cytosolic HMGB1 could function as a modulator to relieve cells from apoptotic stress by inducing autophagy. Particularly, pancreatic beta cells have been well-known to demonstrate the apoptosis to autophagy switch when exposed to hypoxia or lipoxiticy. In this study, we have investigated the beta cells under hypoxic and lipotoxic stress with CCK8 assay and flow cytometry while utilizing a small molecule inhibitor of HMGB1 which can suppress the cytosolic accumulation of HMGB1. The results demonstrated that the cytoplasmic HMGB1 blockade decreased the viability of mouse beta cell line MIN6 and primary islets. Moreover, the cytoplasmic HMGB1 blockade decreased the autophagic flux and increased the ratio of apoptotic MIN6 cells. Also, it was noteworthy that the MIN6 cells have shown high autophagic flux even in basal state. We believe this study linked the role of cytoplasmic HMGB1 in apoptosis to autophagy switch and the importance of autophagy in beta cells under apoptotic stress. We expect this study to open up a novel field of HMGB1 utilization within diabetes- and islet transplantation-related therapeutics, where the current field is mainly focused on the exhaustive blockade of HMGB1.
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WANG, ZHEN, HONG ZHOU, HUAPING ZHENG, XIU TENG, XIAOQIONG WEI, and JIONG LI. "Autophagy-based unconventional secretion of alarmin HMGB1 by keratinocytes plays a pivotal role in psoriatic skin inflammation." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 59.1. http://dx.doi.org/10.4049/jimmunol.202.supp.59.1.
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Abstract The precise mechanism by which autophagy affects psoriasis is poorly understood. Here we show that keratinocytes (KCs) autophagy was activated in psoriatic lesions of patients and mice model, positively correlating with psoriatic severity, and could be inhibited by MAPK family (ERK, p38, JNK) inactivation, implying autophagy was associated with psoriatic inflammation. Indeed, impaired autophagy flux, caused by autophagy inhibitors or KC-specific deletion of Atg5, alleviated psoriasisform inflammation, demonstrating autophagy positively regulated psoriatic inflammation. We then found an autophagy-based unconventional secretory pathway (autosecretion), depended on Atg5 and GRASP55, promoted the psoriasiform KCs inflammation. Moreover, alarmin HMGB1 was more effective than other autosecretory proteins, IL-1β and IL-18, to regulate the psoriasiform cutaneous inflammation. HMGB1 neutralization in autophagy-efficient KCs vanished the psoriasiform inflammation differences between autophagy-efficient KCs and autophagy-deficient KCs. Conversely, recombinant HMGB1 almost completely restored the psoriasiform inflammation in autophagy-deficient KCs in vivo. These results suggested that HMGB1-associated autosecretion, not other intracellular autophagy pathways, played a pivotal role in cutaneous inflammation. Finally, we demonstrated that KC-specific HMGB1 deficient mice, but not DC- or myeloid cell-specific HMGB1 deficient mice, displayed attenuated psoriatic inflammation, due to the essential crosstalk between KC-specific HMGB1-associated autosecretion and γδT cells. Thus, we uncover a novel autophagy mechanism in psoriasis pathogenesis, and imply its clinical significance in psoriasis treatment.
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Toia, Liana M., John Mariano, Michael Weinstein Winter, and Jessica C. Shand. "Alarmin High Mobility Group Box 1 (HMGB1) Activates Alternative NFkB Signaling in Bone Marrow Macrophages in the Leukemia Microenvironment." Blood 126, no. 23 (December 3, 2015): 2204. http://dx.doi.org/10.1182/blood.v126.23.2204.2204.
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Abstract High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) that signals through pattern recognition receptors on monocyte/macrophages to recruit them to sites of tissue injury. In models of sepsis and autoimmunity, HMGB1 can have both immune-activating and regulatory effects depending on the receptor system engaged and the downstream pathway activated. Although chemotherapy-stressed tumor cells are known to release HMGB1, little is known about the effects of tumor-derived HMGB1 on macrophages in the tumor microenvironment. We have previously shown that primary human acute lymphoblastic leukemia cells release high levels of HMGB1 after treatment with anthracycline chemotherapy, and that leukemia-associated HMGB1 induces expression of the IL-1 converting enzyme (caspase-1), consistent with activation of the inflammasome. Paradoxically, inflammatory cytokine production (including IL-1beta) is reduced in this setting. In the present study, we test the hypothesis leukemia-associated HMGB1 activates alternative NFkB signaling through the repressor protein RelB which has been recently shown to silence inflammatory cytokine production via epigenetic effects in sepsis models. To establish proof-of-principle, we first treated primary human bone marrow macrophages (BMM) and THP1 monocytes with 200 ng/ml recombinant HMGB1 (r-HMGB1) in the presence or absence of bacterial lipopolysaccharide (LPS). As predicted, LPS alone increased baseline expression of total NFkB, total p65/RelA and phosphorylated p65/RelA mRNA (20.6 + 7.9-fold by qPCR ddCT, p<0.0001) and protein (measured by Western blot, in BMM and THP1. In contrast, r-HMGB1 treatment produced a significant increase in the expression of RelB mRNA (2.5 + 0.7 fold increase p<0.05) and protein without a significant change in the expression of tNFkB or p65/RelA. Treatment with both r-HMGB1 and LPS maintained this pattern of increased RelB expression without increased expression of p65/RelA, suggesting HMGB1 activity as the dominant effect. Increased RelB expression was unaffected by the addition of an antibody to TLR4, the primary receptor for LPS and a candidate receptor for HMGB1. Next, we determined whether induction of RelB expression also occurs in response to leukemia-derived HMGB1. Immunomagnetically selected ALL cells from the bone marrow of 3 pediatric patients and NALM 6 ALL cells were treated with 20 nM doxorubicin, washed, and placed in culture for 24 hours prior to the addition of BMM in direct coculture. In our model, ALL cells typically release 100-450 ng/ml HMGB1 under these conditions. Again, significantly increased expression of RelB mRNA (6.7 + 2.9 fold, p<0.001) and protein was observed in BMM cultured with doxorubicin-treated ALL cells compared to ALL cells treated with media control, with a corresponding decrease in phospho-IkBa protein expression and unchanged total NFkB, p65/RelA and phosphorylated p65/RelA. Pre-treatment of ALL cells with quercetin, a commercially available flavonoid antioxidant shown to inhibit HMGB1 release, inhibited protein expression of RelB in BMM in a dose-dependent fashion. These data indicate that tumor-derived HMGB1 activates alternative NFkB signaling and is capable of reprogramming the inflammatory response to LPS. Studies are ongoing to the determine downstream effects on macrophage antitumor function to optimize therapeutic reversal of HMGB1 effects and improve the potential for bone marrow macrophages to eradicate residual leukemia that remains after chemotherapy. Disclosures No relevant conflicts of interest to declare.
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Fonken, Laura K., Matthew G. Frank, Meagan M. Kitt, Heather M. D'Angelo, Diana M. Norden, Michael D. Weber, Ruth M. Barrientos, Jonathan P. Godbout, Linda R. Watkins, and Steven F. Maier. "The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming." Journal of Neuroscience 36, no. 30 (July 27, 2016): 7946–56. http://dx.doi.org/10.1523/jneurosci.1161-16.2016.
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Gombert, Jean-Marc, Antoine Thierry, Aurelie Robin, Anne Barra, Thierry Hauet, Guy Touchard, and Andre Herbelin. "Study of alarmin release during ischemia reperfusion injury after human renal transplantation (P2214)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 69.45. http://dx.doi.org/10.4049/jimmunol.190.supp.69.45.
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Abstract The endogenous molecules high-mobility group box 1 (HMGB1) and interleukin-33 (IL-33) have been recognized as alarmins, capable of mediating danger signals during tissue damage. Here, we address their possible role as innate-immune mediators in ischemia-reperfusion injury (IRI) following human kidney transplantation. Urinary HMGB1 and IL-33 levels were significantly increased as soon as 30 min after reperfusion, as compared to prior transplantation. Moreover, a significant correlation was shown between both serum and urinary IL-33 (but not HMGB1) levels and cold ischemia time, from 30 min to 3 days post-tranplantation. In vitro, human umbilical vein endothelial cells submitted to hypoxia-reoxygenation significantly released IL-33. Finally, we can propose that PBMC from renal recipient patients are targeted by both HMGB1 and IL-33 as their receptor (TLR2/4 and ST2-L, respectively) transcripts were enhanced early after transplantation. Consistent with this view, by analyzing iNKT cells, which are been suggested to play a crucial role in IRI and we recently reported to be targeted by IL-33, we showed an early activation state of this innate-like T cell subset in kidney transplant recipients, as attested by the upregulation of CD69 surface expression 1 hour after transplantation. Altogether, these results underline the possible role of IL-33 as an innate-immune mediator during IRI in humans.
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Furci, Fabiana, Giuseppe Murdaca, Corrado Pelaia, Egidio Imbalzano, Girolamo Pelaia, Marco Caminati, Alessandro Allegra, Gianenrico Senna, and Sebastiano Gangemi. "TSLP and HMGB1: Inflammatory Targets and Potential Biomarkers for Precision Medicine in Asthma and COPD." Biomedicines 11, no. 2 (February 2, 2023): 437. http://dx.doi.org/10.3390/biomedicines11020437.
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The airway epithelium, through pattern recognition receptors expressed transmembrane or intracellularly, acts as a first line of defense for the lungs against many environmental triggers. It is involved in the release of alarmin cytokines, which are important mediators of inflammation, with receptors widely expressed in structural cells as well as innate and adaptive immune cells. Knowledge of the role of epithelial cells in orchestrating the immune response and mediating the clearance of invading pathogens and dead/damaged cells to facilitate resolution of inflammation is necessary to understand how, in many chronic lung diseases, there is a persistent inflammatory response that becomes the basis of underlying pathogenesis. This review will focus on the role of pulmonary epithelial cells and of airway epithelial cell alarmins, in particular thymic stromal lymphopoietin (TSLP) and high mobility group box 1 (HMGB1), as key mediators in driving the inflammation of chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), evaluating the similarities and differences. Moreover, emerging concepts regarding the therapeutic role of molecules that act on airway epithelial cell alarmins will be explored for a precision medicine approach in the context of pulmonary diseases, thus allowing the use of these molecules as possible predictive biomarkers of clinical and biological response.
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Suica, Viorel I., Elena Uyy, Luminita Ivan, Raluca M. Boteanu, Aurel Cerveanu-Hogas, Rune Hansen, and Felicia Antohe. "Cardiac Alarmins as Residual Risk Markers of Atherosclerosis under Hypolipidemic Therapy." International Journal of Molecular Sciences 23, no. 19 (September 22, 2022): 11174. http://dx.doi.org/10.3390/ijms231911174.
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Increased levels of low-density lipoproteins are the main risk factor in the initiation and progression of atherosclerosis. Although statin treatment can effectively lower these levels, there is still a residual risk of cardiovascular events. We hypothesize that a specific panel of stress-sensing molecules (alarmins) could indicate the persistence of silent atherosclerosis residual risk. New Zealand White rabbits were divided into: control group (C), a group that received a high-fat diet for twelve weeks (Au), and a treated hyperlipidemic group with a lipid diet for eight weeks followed by a standard diet and hypolipidemic treatment (atorvastatin and PCSK9 siRNA-inhibitor) for four weeks (Asi). Mass spectrometry experiments of left ventricle lysates were complemented by immunologic and genomic studies to corroborate the data. The hyperlipidemic diet determined a general alarmin up-regulation tendency over the C group. A significant spectral abundance increase was measured for specific heat shock proteins, S100 family members, HMGB1, and Annexin A1. The hypolipidemic treatment demonstrated a reversed regulation trend with non-significant spectral alteration over the C group for some of the identified alarmins. Our study highlights the discriminating potential of alarmins in hyperlipidemia or following hypolipidemic treatment. Data are available via ProteomeXchange with identifier PXD035692.
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Yang, De, Yana Li, Yingjie Nie, Anna Trivett, and Joost J. Oppenheim. "Keratinocyte Release of Alarmin HMGN1 Is triggered by Elevation of Intracellular Calcium." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 203.19. http://dx.doi.org/10.4049/jimmunol.196.supp.203.19.
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Abstract Intra-nuclear high-mobility group nucleosome-binding 1 (HMGN1) functions as a chromatin modulator to regulate gene expression, whereas extracellular HMGN1 acts as an alarmin and contributes to the induction of antigen-specific immune responses. However, aside from passive release resulting from cell injury, it is unclear whether HMGN1 is released extracellularly by viable cells. In this study, we studied the cell type(s) capable of releasing HMGN1 and the underlying mechanism(s). Using a keratinocyte cell line KERTr, we found that ionomycin could induce the release of HMGN1 without changing its expression at the mRNA level. This release occurred in the absence of cell death. Other stimulants capable of elevating intracellular calcium such as ATP or SDF-1α also induced HMGN1 release. HMGN1 release was dependent on calcium/calmodulin and JAK2. The capacity of ionomycin and ATP to induce HMGN1 release was confirmed using cultured primary keratinocytes. Interestingly, macrophages could not release HMGN1 in response to these diverse stimuli. Thus, HMGN1 is preferentially released by keratinocytes, but not by leukocytes such as macrophages, in response to elevation of intracellular calcium.
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Gangemi, Sebastiano, Marco Casciaro, Giovanni Trapani, Sebastiano Quartuccio, Michele Navarra, Giovanni Pioggia, and Egidio Imbalzano. "Association between HMGB1 and COPD: A Systematic Review." Mediators of Inflammation 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/164913.
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HMGB1 is an alarmin, a protein that warns and activates inflammation. Chronic obstructive pulmonary disease (COPD) is characterised by a progressive airflow obstruction and airway inflammation. Current anti-inflammatory therapies are poorly effective in maintaining lung function and symptoms of COPD. This underlines the need for finding new molecular targets involved in disease pathogenesis in order to block pathology progression. This review aims to analyse latest advances on HMGB1 role, utilisation, and potential application in COPD. To this purpose we reviewed experimental studies that investigated this alarmin as marker as well as a potential treatment in chronic obstructive pulmonary disease. This systematic review was conducted according to PRISMA guidelines. In almost all the studies, it emerged that HMGB1 levels are augmented in smokers and in patients affected by COPD. It emerged that cigarette smoking, the most well-known causative factor of COPD, induces neutrophils death and necrosis. The necrosis of neutrophil cells leads to HMGB1 release, which recruits other neutrophils in a self-maintaining process. According to the results reported in the paper both inhibiting HMGB1 and its receptor (RAGE) and blocking neutrophils necrosis (inducted by cigarette smoking) could be the aim for further studies.
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Galaz, Jose, Roberto Romero, Marcia Arenas-Hernandez, Bogdan Panaitescu, Robert Para, and Nardhy Gomez-Lopez. "Betamethasone as a potential treatment for preterm birth associated with sterile intra-amniotic inflammation: a murine study." Journal of Perinatal Medicine 49, no. 7 (April 20, 2021): 897–906. http://dx.doi.org/10.1515/jpm-2021-0049.
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Abstract Objectives Preterm birth remains the leading cause of perinatal morbidity and mortality worldwide. Preterm birth is preceded by spontaneous preterm labor, which is commonly associated with sterile intra-amniotic inflammation; yet, no approved treatment exists for this clinical condition. Corticosteroids are the standard of care to improve neonatal outcomes in women at risk of preterm birth. Herein, we first validated our model of alarmin-induced preterm birth. Next, we investigated whether treatment with betamethasone could prevent preterm birth resulting from sterile intra-amniotic inflammation in mice. Methods Under ultrasound guidance, the first cohort of dams received an intra-amniotic injection of the alarmin high-mobility group box-1 (HMGB1, n=10) or phosphate-buffered saline (PBS, n=9) as controls. A second cohort of dams received HMGB1 intra-amniotically and were subcutaneously treated with betamethasone (n=15) or vehicle (n=15). Dams were observed until delivery, and perinatal outcomes were observed. Results Intra-amniotic HMGB1 reduced gestational length (p=0.04), inducing preterm birth in 40% (4/10) of cases, of which 100% (4/4) were categorized as late preterm births. Importantly, treatment with betamethasone extended the gestational length (p=0.02), thereby reducing the rate of preterm birth by 26.6% (from 33.3% [5/15] to 6.7% [1/15]). Treatment with betamethasone did not worsen the rate of neonatal mortality induced by HMGB1 or alter weight gain in the first three weeks of life. Conclusions Treatment with betamethasone prevents preterm birth induced by the alarmin HMGB1. This study supports the potential utility of betamethasone for treating women with sterile intra-amniotic inflammation.
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Lamkanfi, Mohamed, Anasuya Sarkar, Lieselotte Vande Walle, Alberto C. Vitari, Amal O. Amer, Mark D. Wewers, Kevin J. Tracey, Thirumala-Devi Kanneganti, and Vishva M. Dixit. "Inflammasome-Dependent Release of the Alarmin HMGB1 in Endotoxemia." Journal of Immunology 185, no. 7 (August 27, 2010): 4385–92. http://dx.doi.org/10.4049/jimmunol.1000803.
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Harris, Helena Erlandsson, Ulf Andersson, and David S. Pisetsky. "HMGB1: A multifunctional alarmin driving autoimmune and inflammatory disease." Nature Reviews Rheumatology 8, no. 4 (January 31, 2012): 195–202. http://dx.doi.org/10.1038/nrrheum.2011.222.
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Allegra, Alessandro, Giuseppe Murdaca, Luca Gammeri, Roberta Ettari, and Sebastiano Gangemi. "Alarmins and MicroRNAs, a New Axis in the Genesis of Respiratory Diseases: Possible Therapeutic Implications." International Journal of Molecular Sciences 24, no. 2 (January 16, 2023): 1783. http://dx.doi.org/10.3390/ijms24021783.
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It is well ascertained that airway inflammation has a key role in the genesis of numerous respiratory pathologies, including asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome. Pulmonary tissue inflammation and anti-inflammatory responses implicate an intricate relationship between local and infiltrating immune cells and structural pulmonary cells. Alarmins are endogenic proteins discharged after cell injury in the extracellular microenvironment. The purpose of our review is to highlight the alterations in respiratory diseases involving some alarmins, such as high mobility group box 1 (HMGB1) and interleukin (IL)-33, and their inter-relationships and relationships with genetic non-coding material, such as microRNAs. The role played by these alarmins in some pathophysiological processes confirms the existence of an axis composed of HMGB1 and IL-33. These alarmins have been implicated in ferroptosis, the onset of type 2 inflammation and airway alterations. Moreover, both factors can act on non-coding genetic material capable of modifying respiratory function. Finally, we present an outline of alarmins and RNA-based therapeutics that have been proposed to treat respiratory pathologies.
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Ma, Huan, Ning Cheng, and Caiyi Zhang. "Schizophrenia and Alarmins." Medicina 58, no. 6 (May 24, 2022): 694. http://dx.doi.org/10.3390/medicina58060694.
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Schizophrenia, consisting of a group of severe psychiatric disorders with a complex etiology, is a leading cause of disability globally. Due to the lack of objective indicators, accurate diagnosis and selection of effective treatments for schizophrenia remain challenging. The association between schizophrenia and alarmins levels has been proposed for many years, but without solid evidence. Alarmins are prestored molecules that do not require processing and can be released upon cell death or damage, making them an ideal candidate for an early initiator of inflammation. Immunological biomarkers seem to be related to disease progression and treatment effectiveness. Several studies suggest strong associations among the high-mobility group box 1 protein (HMGB1), interleukin-1α, interleukin-33, S100B, heat-shock proteins, and uric acid with schizophrenic disorders. The purpose of this review is to discuss the evidence of central and peripheral immune findings in schizophrenia, their potential causes, and the effects of immunomodulatory therapies on symptoms and outline potential applications of these markers in managing the illness. Although there are currently no effective markers for diagnosing or predicting treatment effects in patients with schizophrenia, we believe that screening immune-inflammatory biomarkers that are closely related to the pathological mechanism of schizophrenia can be used for early clinical identification, diagnosis, and treatment of schizophrenia, which may lead to more effective treatment options for people with schizophrenia.
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Yang, De, Michael Bustin, and Joost J. Oppenheim. "Harnessing the alarmin HMGN1 for anticancer therapy." Immunotherapy 7, no. 11 (November 2015): 1129–31. http://dx.doi.org/10.2217/imt.15.76.
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Rabadi, May M., Mei-Chuan Kuo, Tammer Ghaly, Seham M. Rabadi, Mia Weber, Michael S. Goligorsky, and Brian B. Ratliff. "Interaction between uric acid and HMGB1 translocation and release from endothelial cells." American Journal of Physiology-Renal Physiology 302, no. 6 (March 15, 2012): F730—F741. http://dx.doi.org/10.1152/ajprenal.00520.2011.
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We aimed to investigate the potential relationship between alarmins [acting via Toll-like receptor-4 (TLR4)], uric acid (UA), and high-mobility group box-1 protein (HMGB1) during acute kidney injury. UA, which is significantly increased in the circulation following renal ischemia-reperfusion injury (IRI), was used both in vitro and in vivo as an early response-signaling molecule to determine its ability to induce the secretion of HMGB1 from endothelial cells. Treatment of human umbilical vein endothelial cells (HUVEC) with UA resulted in increased HMGB1 mRNA expression, acetylation of nuclear HMGB1, and its subsequent nuclear-cytoplasmic translocation and release into the circulation, as determined by Western blotting and immunofluorescence. Treatment of HUVEC with UA and a calcium mobilization inhibitor (TMB-8) or a MEK/Erk pathway inhibitor (U0126) prevented translocation of HMGB1 from the nucleus, resulting in reduced cytoplasmic and circulating levels of HMGB1. Once released, HMGB1 in autocrine fashion promoted further HMGB1 release while also stimulating NF-κB activity and increased angiopoietin-2 expression and protein release. Transfection of HUVEC with TLR4 small interfering (si) RNA reduced HMGB1 levels during UA and HMGB1 treatment. In summary, UA after IRI mediates the acetylation and release of HMGB1 from endothelial cells by mechanisms that involve calcium mobilization, the MEK/Erk pathway, and activation of TLR4. Once released, HMGB1 promotes its own further cellular release while acting as an autocrine and paracrine to activate both proinflammatory and proreparative mediators.
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Holmannová, Drahomíra, Barbora Císařová, Pavel Borský, Zdeněk Fiala, Ctirad Andrýs, Květoslava Hamaková, Tereza Švadláková, et al. "Goeckerman Regimen Reduces Alarmin Levels and PASI Score in Paediatric Patients with Psoriasis." Acta Medica (Hradec Kralove, Czech Republic) 64, no. 4 (2021): 204–12. http://dx.doi.org/10.14712/18059694.2022.3.
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Background. Psoriasis is a chronic systemic inflammatory disease with (extra-)cutaneous manifestations. Inflammation is associated with cellular stress and tissue damage which lead to the release of alarmins (signals of danger). Goeckerman regimen (GR) is a highly efficacious treatment consisting of the application of pharmaceutical crude tar and UVB light exposure. The reduction of inflammatory processes in the skin is accompanied by changes in the levels of inflammatory markers - alarmins (HMBG-1, S100A7, S1000A8, S100A9, S100A12, IL-17, IL-22, and IL-33). Methods. The alarmin levels in sera of 19 paediatric patients with psoriasis were determined before and after GR using commercial ELISA kits. The Psoriasis area severity index (PASI) was used to determine the disease severity. Results. GR reduced both PASI and the levels of all measured alarmins. The levels of S100A7, S100A9, IL-22, IL-33, and HMGB-1 were significantly decreased. Positive correlations between IL-22 and PASI, between S100A9 and IL-17, S100A9 and IL-22, and a negative correlation between S100A8 and IL-33 were found. Conclusions. Goeckerman regimen is a very effective, safe and low-cost therapy. We confirmed, it modulates the immune system reactivity, ameliorates the severity of the disease and reduces the levels of alarmins reflecting the presence and intensity of inflammation.
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shi, guilan, Kennady Abbott, Russell D. Salter, and Peter A. Keyel. "Inflammasome dependent IL-1β secretion requires Dnase1L3 activity." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 62.14. http://dx.doi.org/10.4049/jimmunol.196.supp.62.14.
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Abstract Inflammation is driven by inflammatory cell death and the secretion of pro-inflammatory cytokines like IL-1β and alarmins like High Mobility Group Box Protein 1 (HMGB1) by the inflammasome. The inflammasome is a cytosolic multiprotein complex that typically contains a Nod-like receptor (NLR), like NLRP3 or NLRC4, and the adaptor ASC which links to caspase-1 for activation. How signals from the cytoplasmic NLR induce nuclear ASC and HMGB1 translocation into the cytosol for inflammasome function remains elusive. Here we hypothesize that Dnase1L3 (DNase γ), a Ca2+/Mg2+-dependent endonuclease, facilitates inflammasome-mediated release of cytokines and alarmins. When we treated murine macrophages with the Dnase1L3 inhibitors Fmoc-D-cyclohexylalanine (FCA) or pontacyl violet 6R (PV), HMGB1 and IL-1β release were inhibited following NLRP3 or NLRC4 stimulation. FCA and PV did not directly inhibit Casp1. We confirmed the specificity of the inhibitors using RNAi silencing of Dnase1L3 in THP-1 cell lines. Interestingly, pyroptosis was only slightly blocked by Dnase1L3 inhibition. Mechanistically, we found that ASC nuclear translocation and speck formation was impaired following FCA treatment, as was Casp1 cleavage. These data suggest that Dnase1L3 inhibition prevents Asc release from the nucleus. This demonstrates that pyroptosis and cytokine release can be mechanistically separated. Taken all together, these data show that Dnase1L3 is necessary for inflammasome-mediated release of cytokines and alarmins.
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Parker, Katherine, Lucas Horn, Virginia Clements, Pratima Sinha, Huan Yang, Jianhua Li, Kevin Tracey, and Suzanne Ostrand-Rosenberg. "Inhibition of HMGB1 delays tumor progression, reduces MDSC-mediated immune suppression, and diminishes MDSC-macrophage cross-talk (P2001)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 53.1. http://dx.doi.org/10.4049/jimmunol.190.supp.53.1.
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Abstract Tumor-induced immune suppression is driven by immune suppressive cells including Myeloid-Derived Suppressor Cells (MDSC). MDSC are present in most patients with cancer. They block T cell activation and drive type 2 immunity. Cross-talk with macrophages enhances MDSC secretion of pro-tumor molecules such as IL-10 and decreases macrophage production of IL-12. Because the alarmin HMGB1 is increased in many cancers, we are determining if HMGB1 drives MDSC. Treatment of BALB/c mice with 4T1 mammary carcinoma with HMGB1 inhibitors Glycyrrhizin or Ethyl Pyruvate reduced lung metastases, while treatment of C57BL/6 mice with MC38 colon carcinoma with an HMGB1 neutralizing antibody (2G7) reduced MDSC levels in the blood, spleen, and tumor. BALB/c mice carrying 4T1 tumor cells down-regulated for HMGB1 by shRNA had an extended survival time relative to mice with irrelevant shRNA 4T1 tumor. Treatment of MC38 tumor-bearing mice with the anti-inflammatory A box domain of HMGB1 reduced primary tumor growth. In in vitro experiments, HMGB1 inhibitors decreased cross-talk-induced IL-10 production by MDSC and IL-6 production by macrophages, and reduced MDSC suppressive potency for T cells. HMGB1 inhibitors also reduced MDSC differentiation from bone marrow progenitor cells. These findings indicate that full-length HMGB1 drives tumor progression, while the anti-inflammatory A box domain counteracts full-length HMGB1 and reduces tumor growth and MDSC accumulation.
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Garcia-Flores, Valeria, Zhenjie Liu, Roberto Romero, Yi Xu, Derek Miller, Jose Galaz, Andrew Winters, Marcelo Farias-Jofre, Kevin Theis, and Nardhy Gomez-Lopez. "M2-polarized macrophages prevent preterm birth and improve neonatal survival and immunity." Journal of Immunology 212, no. 1_Supplement (May 1, 2024): 0355_5259. http://dx.doi.org/10.4049/jimmunol.212.supp.0355.5259.
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Abstract Preterm birth (PTB), commonly preceded by preterm labor, is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm labor are associated with sterile intra-amniotic inflammation (SIAI), an inflammatory condition without detectable microorganisms. To date, no successful strategies to treat SIAI have been developed. Herein, we present mechanistic proof that treatment with M2-polarized macrophages (M2 MΦ) can effectively prevent PTB [(HMGB1, n = 28 vs. HMGB1+M2 MΦ, n = 29) (p<0.05)] and neonatal mortality [(HMGB1, n = 20 litters vs. HMGB1+M2 MΦ, n = 14 litters) (p<0.001)] induced by the ultrasound-guided intra-amniotic injection of the alarmin HMGB1 in mice. M2 MΦ halt the premature pathway of labor by infiltrating maternal and fetal compartments, where they inhibit NLRP3 inflammasome activation triggered by HMGB1. Furthermore, M2 MΦ dampen the HMGB1-induced inflammatory response in the amniotic cavity and fetal lung. Notably, neonates exposed to HMGB1 in utero display a reduced capacity to clear bacterial infection and gut microbiome dysbiosis, which are restored by M2 MΦ treatment [(HMGB1, n = 10 vs. HMGB1+ M2 MΦ, n = 10) (p<0.001 and p<0.01, respectively)]. Our findings provide cogent evidence that M2 MΦ can serve as a cellular strategy to mitigate PTB and decrease neonatal mortality.
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Karagyozov, Luchezar, and Jordana Todorova. "Computational Analysis of the Messenger RNA Variants Encoding Two Isoforms of the High-mobility Group box 1 Protein." Natural Science and Advanced Technology Education 30, no. 3 (July 1, 2021): 243–52. http://dx.doi.org/10.53656/nat2021-3.02.
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High-mobility group box 1 protein (HMGB1) is a multifunctional nonhistone chromosomal protein. This widespread nuclear protein has a dual function-in the nucleus - it binds DNA and participates in practically all DNA-dependent processes. On the other hand, the protein plays an important role in the extracellular matrix as an “alarmin”, which interacts with certain receptors and stimulates biochemical pathways, associated with carcinogenesis and metastasis. HMGB1 is a critical damage-associated molecular pattern molecule, has been implicated in several inflammatory diseases and cancer types. This universality makes it an attractive target for innovative therapeutic strategies in the treatment of various diseases. The updated database for the HMGB1 gene, encoding the high-mobility group box 1 protein, was used for computational analysis of the annotated mRNA splice variants. Results showed that five of the splice variants encode an HMGB1 protein, containing 215 amino acid residues. However, two of the splice variants encode a shorter HMGB1 protein with 158 residues. Presently, the existence of a shorter HMGB1 protein is not registered in the protein databanks. This inconsistency is not yet resolved.
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Światły, Agata, Norbert Wąsik, Joanna Hajduk, Eliza Matuszewska, Paweł Dereziński, Bartosz Sokół, Roman Jankowski, Zenon Kokot, and Jan Matysiak. "Mass spectrometry analysis of redox forms of High-Mobility Group Box-1 Protein in cerebrospinal fluid: initial experience." Journal of Medical Science 88, no. 3 (March 12, 2019): 171–76. http://dx.doi.org/10.20883/jms.311.
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Introduction. High-mobility group box 1 (HMGB1) is an alarmin with proinflammatory potential determined by redox status of the cysteines at position 23 and 45. It may also play a role as a biomarker in biological fluids. The aim of this study was the identification of different HMGB1 redox forms in cerebrospinal fluid (CSF) obtained from subarachnoid hemorrhage patients.
Material and Methods. 6 CSF samples were collected from aneurysmal subarachnoid haemorrhage patients. Commercially available HMGB1 isoforms served as a positive control. Immunoprecipitation and electrophoretic isolation of HMGB1 protein were performed, then both CSF and control were analyzed using mass spectrometry technique. To distinguish between fully reduced (thiol group at C23 and C45) and disulfide (disulfide bond connecting C23 and C45) HMGB1 forms, top-down sequencing of the spectra was performed.
Results. Top-down sequencing analysis allowed to distinguish between HMGB1 isoforms only in commercially available standard without preceding immunoprecipitation and electrophoresis. MALDI spectra differ i.e. on the fully reduced HMGB1 spectrum fragmentation occurs before and beyond C22, which is not present on the disulfide HMGB1 spectrum. Analysis of HMGB1 isolated from CSF obtained from subarachnoid hemorrhage patients gave no results.
Conclusions. Top-down sequencing enables to distinguish between redox forms of HMGB1. Electrophoresis and tryptic digestion cannot precede mass spectrometry analysis of redox forms of HMGB1 due to the reduction of disulfide bonds during these processes. Preferred method of isolation of HMGB1 for direct analysis using top-down sequencing mustn’t include protein digestion or degradation.
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Taverna, Simona, Alessandro Tonacci, Maria Ferraro, Giuseppe Cammarata, Giuseppina Cuttitta, Salvatore Bucchieri, Elisabetta Pace, and Sebastiano Gangemi. "High Mobility Group Box 1: Biological Functions and Relevance in Oxidative Stress Related Chronic Diseases." Cells 11, no. 5 (March 1, 2022): 849. http://dx.doi.org/10.3390/cells11050849.
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In the early 1970s, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and named high-mobility group (HMG) proteins. High-mobility group box 1 (HMGB1) is the most studied HMG protein that detects and coordinates cellular stress response. The biological function of HMGB1 depends on its subcellular localization and expression. It plays a critical role in the nucleus and cytoplasm as DNA chaperone, chromosome gatekeeper, autophagy maintainer, and protector from apoptotic cell death. HMGB1 also functions as an extracellular alarmin acting as a damage-associated molecular pattern molecule (DAMP). Recent findings describe HMGB1 as a sophisticated signal of danger, with a pleiotropic function, which is useful as a clinical biomarker for several disorders. HMGB1 has emerged as a mediator in acute and chronic inflammation. Furthermore, HMGB1 targeting can induce beneficial effects on oxidative stress related diseases. This review focus on HMGB1 redox status, localization, mechanisms of release, binding with receptors, and its activities in different oxidative stress-related chronic diseases. Since a growing number of reports show the key role of HMGB1 in socially relevant pathological conditions, to our knowledge, for the first time, here we analyze the scientific literature, evaluating the number of publications focusing on HMGB1 in humans and animal models, per year, from 2006 to 2021 and the number of records published, yearly, per disease and category (studies on humans and animal models).
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Bode, Michael, David Haenel, Christoph E. Hagemeyer, Hannah Seeba, Daniel Duerschmied, Nicole Bassler, Karin A. Jandeleit-Dahm, et al. "HMGB1 binds to activated platelets via the receptor for advanced glycation end products and is present in platelet rich human coronary artery thrombi." Thrombosis and Haemostasis 114, no. 11 (2015): 994–1003. http://dx.doi.org/10.1160/th14-12-1073.
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SummaryHigh mobility group box 1 (HMGB1) acts as both a nuclear protein that regulates gene expression, as well as a pro-inflammatory alarmin that is released from necrotic or activated cells. Recently, HMGB1-expression in human atherosclerotic plaques was identified. Therapeutic blockade of HMGB1 reduced the development of diet-induced atherosclerosis in ApoE knockout mice. Thus, we hypothesised an interaction between HMGB1 and activated platelets. Binding of recombinant HMGB1 to platelets was assessed by flow cytometry. HMGB1 bound to thrombin-activated human platelets (MFI 2.49 vs 25.01, p=0.0079). Blood from wild-type, TLR4 and RAGE knockout mice was used to determine potential HMGB1 receptors on platelets. HMGB1 bound to platelets from wild type C57Bl6 (MFI 2.64 vs 20.3, p< 0.05), and TLR4-/- mice (MFI 2.11 vs 25.65, p< 0.05) but failed to show binding to platelets from RAGE-/- mice (p > 0.05). RAGE expression on human platelets was detected by RT-PCR with mRNA extracted from highly purified platelets and confirmed by Western blot and immunofluorescence microscopy. Platelet activation increased RAGE surface expression (MFI 4.85 vs 6.74, p< 0.05). Expression of HMGB1 in human coronary artery thrombi was demonstrated by immunohistochemistry and revealed high expression levels. Platelets bind HMGB1 upon thrombin-induced activation. Platelet specific expression of RAGE could be detected at the mRNA and protein level and is involved in the binding of HMGB1. Furthermore, platelet activation up-regulates platelet surface expression of RAGE. HMGB1 is highly expressed in platelet-rich human coronary artery thrombi pointing towards a central role for HMGB1 in atherothrombosis, thereby suggesting the possibility of platelet targeted anti-inflammatory therapies for atherothrombosis.
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Arnold, Edward A., Robin J. Kaai, Katie Leung, Mia R. Brinkley, Laurel E. Kelnhofer-Millevolte, Monica S. Guo, and Daphne C. Avgousti. "Adenovirus protein VII binds the A-box of HMGB1 to repress interferon responses." PLOS Pathogens 19, no. 9 (September 13, 2023): e1011633. http://dx.doi.org/10.1371/journal.ppat.1011633.
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Viruses hijack host proteins to promote infection and dampen host defenses. Adenovirus encodes the multifunctional protein VII that serves both to compact viral genomes inside the virion and disrupt host chromatin. Protein VII binds the abundant nuclear protein high mobility group box 1 (HMGB1) and sequesters HMGB1 in chromatin. HMGB1 is an abundant host nuclear protein that can also be released from infected cells as an alarmin to amplify inflammatory responses. By sequestering HMGB1, protein VII prevents its release, thus inhibiting downstream inflammatory signaling. However, the consequences of this chromatin sequestration on host transcription are unknown. Here, we employ bacterial two-hybrid interaction assays and human cell culture to interrogate the mechanism of the protein VII-HMGB1 interaction. HMGB1 contains two DNA binding domains, the A- and B-boxes, that bend DNA to promote transcription factor binding while the C-terminal tail regulates this interaction. We demonstrate that protein VII interacts directly with the A-box of HMGB1, an interaction that is inhibited by the HMGB1 C-terminal tail. By cellular fractionation, we show that protein VII renders A-box containing constructs insoluble, thereby acting to prevent their release from cells. This sequestration is not dependent on HMGB1’s ability to bind DNA but does require post-translational modifications on protein VII. Importantly, we demonstrate that protein VII inhibits expression of interferon β, in an HMGB1-dependent manner, but does not affect transcription of downstream interferon-stimulated genes. Together, our results demonstrate that protein VII specifically harnesses HMGB1 through its A-box domain to depress the innate immune response and promote infection.
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Kvivik, Ingeborg, Grete Jonsson, Roald Omdal, and Cato Brede. "Sample Preparation Strategies for Antibody-Free Quantitative Analysis of High Mobility Group Box 1 Protein." Pharmaceuticals 14, no. 6 (June 3, 2021): 537. http://dx.doi.org/10.3390/ph14060537.
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Sickness behavior and fatigue are induced by cerebral mechanisms involving inflammatory cytokines. High mobility group box 1 (HMGB1) is an alarmin, and a potential key player in this process. Reliable quantification methods for total HMGB1 and its redox variants must be established in order to clearly understand how it functions. Current methods pose significant challenges due to interference from other plasma proteins and autoantibodies. We aimed to develop an antibody-free sample preparation method followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to measure HMGB1 in human plasma. Different methods were applied for the removal of interfering proteins and the enrichment of HMGB1 from spiked human plasma samples. A comparison of methods showed an overall low extraction recovery (<40%), probably due to the stickiness of HMGB1. Reversed-phase liquid chromatography separation of intact proteins in diluted plasma yielded the most promising results. The method produced an even higher degree of HMGB1 purification than that observed with immunoaffinity extraction. Detection sensitivity needs to be further improved for the measurement of HMGB1 in patient samples. Nevertheless, it has been demonstrated that a versatile and fully antibody-free sample preparation method is possible, which could be of great use in further investigations.
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Manganelli, Valeria, Antonella Capozzi, Simona Truglia, Cristiano Alessandri, Emanuela Lococo, Tina Garofalo, Caterina De Carolis, et al. "Elevated Serum Level of HMGB1 in Patients with the Antiphospholipid Syndrome." Journal of Immunology Research 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/4570715.
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Pregnancy problems are common in patients with rheumatic disease; indeed, autoimmune disorders and autoantibodies can affect pregnancy progress and lead to maternal complications. Recent studies have highlighted a close association between HMGB1, chronic inflammation, and autoimmune diseases. Thus, in this investigation, we analyzed serum levels of HMGB1, an alarmin which plays a pivotal role in inducing and enhancing immune cell function. Sera from 30 patients with antiphospholipid syndrome (11 primary and 19 secondary APS), 35 subjects with pregnancy morbidity, and 30 healthy women were analysed for HMGB1 and its putative receptor RAGE (sRAGE) by Western blot and for TNF-α by ELISA. Results revealed that APS patients showed significantly increased serum levels of HMGB1, sRAGE, and the proinflammatory cytokine TNF-α, as compared to healthy women. However, also, the pregnancy morbidity subjects showed significantly increased levels of HMGB1 and sRAGE as well as TNF-α compared to healthy women. Our findings suggest that in subjects with pregnancy morbidity, including obstetric APS, elevated levels of HMGB1/sRAGE may represent an alarm signal, indicating an increase of proinflammatory triggers. Further studies are needed to evaluate the role of HMGB1/sRAGE as a possible tool to evaluate the risk stratification of adverse pregnancy outcomes.
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Bertheloot, Damien, and Eicke Latz. "HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins." Cellular & Molecular Immunology 14, no. 1 (August 29, 2016): 43–64. http://dx.doi.org/10.1038/cmi.2016.34.
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Sung, Mia, Mahamat Babagana, Kyu-Seon Oh, Sayantan Chakraborty, Alicja Pacholewska, Takashi Furusawa, and Michael Bustin. "Functional macrophage chromatin landscapes depend on HMGN1/HMGN2." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 69.10. http://dx.doi.org/10.4049/jimmunol.204.supp.69.10.
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Abstract The High Mobility Group (HMG) proteins are ubiquitously present in the nuclei of all vertebrate cells. HMG proteins bind dynamically to chromatin without DNA sequence specificity, and they affect DNA-dependent functions such as replication, repair, and transcription, but only in the context of chromatin. HMGs are also suggested to play an important role in the immune system. Both HMGB1 and HMGN1 can act as alarmins. HMGN proteins also affect the response of B lymphocytes to bacterial LPS stimulation. HMGN proteins are typically enriched at regulatory sites such as enhancers and promoters, and have been shown to affect the chromatin landscape, suggesting a role in epigenetic regulatory processes. In LPS-stimulated bone marrow-derived macrophages (BMDMs), most HMG genes are downregulated in response to LPS (Oh KS et al, 2017 Immunity, PMID: 28801231. To understand the role of HMG proteins in the regulation of macrophage chromatin, we performed RNA-seq and ATAC-seq on BMDMs and two tissue-resident macrophage populations from mice lacking both HMGN1 and HMGN2. We identified several hundred differentially expressed genes in BMDMs with a large gene cluster showing female-specific downregulation in the double knockout. In peritoneal macrophages, the largest differentially expressed gene cluster was from the female-specific upregulated genes. The most dramatic transcriptome-wide changes were observed in microglia. Interestingly, MHC genes were commonly upregulated in macrophages from mutant mice. Together with alterations in chromatin, this raises the possibility that HMGNs maintain functional macrophage enhancers with specificity for the resident tissue.
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Gougeon, M.-L., M.-T. Melki, and H. Saïdi. "HMGB1, an alarmin promoting HIV dissemination and latency in dendritic cells." Cell Death & Differentiation 19, no. 1 (October 28, 2011): 96–106. http://dx.doi.org/10.1038/cdd.2011.134.
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Horiuchi, Takahiro, Natsumi Sakata, Yoshihiro Narumi, Tomohiro Kimura, Takashi Hayashi, Keisuke Nagano, Keyue Liu, et al. "Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity." Journal of Biological Chemistry 292, no. 20 (April 3, 2017): 8436–46. http://dx.doi.org/10.1074/jbc.m116.769380.
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Peng, Travis, Shin-Yi Du, Myoungsun Son, and Betty Diamond. "HIF-1α is a negative regulator of interferon regulatory factors: Implications for interferon production by hypoxic monocytes." Proceedings of the National Academy of Sciences 118, no. 26 (June 9, 2021): e2106017118. http://dx.doi.org/10.1073/pnas.2106017118.
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Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1β, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.
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Kondratska, O. A., N. G. Grushka, V. V. Veshko, S. I. Pavlovych, and R. I. Yanchii. "MULTIFUNCTIONAL ACTIVITY OF NUCLEAR PROTEIN AMPHOTERIN AND ITS ROLE IN ENDOTOXEMIA." Fiziolohichnyĭ zhurnal 69, no. 6 (November 10, 2023): 120–32. http://dx.doi.org/10.15407/fz69.06.120.
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The review summarizes generalizing modern scientific data on the main functions of the protein HMGB1, and its physiological and pathological roles. Amphoterin is involved in key processes that ensure the functioning of DNA in the cell nucleus and plays an important role outside it. HMGB1 has been implicated in many human inflammatory diseases such as sepsis, ischemic reperfusion injury, neurological conditions, cardiovascular disease, autoimmune disease, and others. This manuscript describes the structure and main functions of HMGB1, discusses the significance of this alarmin as damage-associated molecular patterns, and analyzes its role in the development of inflammation and cell death. Special attention is focused on the role of HMGB1 in the development of endotoxemia, as well as data on the signaling pathways involved in its pathogenesis. Information on the results of studies of the possibility of modulating the activity of this protein using inhibitors is also considered, since understanding this may be useful for developing new therapeutic strategies aimed at treating inflammatory conditions of various origins.
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Careccia, Giorgia, Marielle Saclier, Mario Tirone, Elena Ruggieri, Elisa Principi, Lizzia Raffaghello, Silvia Torchio, et al. "Rebalancing expression of HMGB1 redox isoforms to counteract muscular dystrophy." Science Translational Medicine 13, no. 596 (June 2, 2021): eaay8416. http://dx.doi.org/10.1126/scitranslmed.aay8416.
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Muscular dystrophies (MDs) are a group of genetic diseases characterized by progressive muscle wasting associated to oxidative stress and persistent inflammation. It is essential to deepen our knowledge on the mechanism connecting these two processes because current treatments for MDs have limited efficacy and/or are associated with side effects. Here, we identified the alarmin high-mobility group box 1 (HMGB1) as a functional link between oxidative stress and inflammation in MDs. The oxidation of HMGB1 cysteines switches its extracellular activities from the orchestration of tissue regeneration to the exacerbation of inflammation. Extracellular HMGB1 is present at high amount and undergoes oxidation in patients with MDs and in mouse models of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy 3 (LGMDR3) compared to controls. Genetic ablation of HMGB1 in muscles of DMD mice leads to an amelioration of the dystrophic phenotype as evidenced by the reduced inflammation and muscle degeneration, indicating that HMGB1 oxidation is a detrimental process in MDs. Pharmacological treatment with an engineered nonoxidizable variant of HMGB1, called 3S, improves functional performance, muscle regeneration, and satellite cell engraftment in dystrophic mice while reducing inflammation and fibrosis. Overall, our data demonstrate that the balance between HMGB1 redox isoforms dictates whether skeletal muscle is in an inflamed or regenerating state, and that the nonoxidizable form of HMGB1 is a possible therapeutic approach to counteract the progression of the dystrophic phenotype. Rebalancing the HMGB1 redox isoforms may also be a therapeutic strategy for other disorders characterized by chronic oxidative stress and inflammation.
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Kochi, Takahiro, Yoki Nakamura, Simeng Ma, Kazue Hisaoka-Nakashima, Dengli Wang, Keyue Liu, Hidenori Wake, Masahiro Nishibori, Masahiro Irifune, and Norimitsu Morioka. "Pretreatment with High Mobility Group Box-1 Monoclonal Antibody Prevents the Onset of Trigeminal Neuropathy in Mice with a Distal Infraorbital Nerve Chronic Constriction Injury." Molecules 26, no. 7 (April 2, 2021): 2035. http://dx.doi.org/10.3390/molecules26072035.
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Persistent pain following orofacial surgery is not uncommon. High mobility group box 1 (HMGB1), an alarmin, is released by peripheral immune cells following nerve injury and could be related to pain associated with trigeminal nerve injury. Distal infraorbital nerve chronic constriction injury (dIoN-CCI) evokes pain-related behaviors including increased facial grooming and hyper-responsiveness to acetone (cutaneous cooling) after dIoN-CCI surgery in mice. In addition, dIoN-CCI mice developed conditioned place preference to mirogabalin, suggesting increased neuropathic pain-related aversion. Treatment of the infraorbital nerve with neutralizing antibody HMGB1 (anti-HMGB1 nAb) before dIoN-CCI prevented both facial grooming and hyper-responsiveness to cooling. Pretreatment with anti-HMGB1 nAb also blocked immune cell activation associated with trigeminal nerve injury including the accumulation of macrophage around the injured IoN and increased microglia activation in the ipsilateral spinal trigeminal nucleus caudalis. The current findings demonstrated that blocking of HMGB1 prior to nerve injury prevents the onset of pain-related behaviors, possibly through blocking the activation of immune cells associated with the nerve injury, both within the CNS and on peripheral nerves. The current findings further suggest that blocking HMGB1 before tissue injury could be a novel strategy to prevent the induction of chronic pain following orofacial surgeries.