scholarly journals Leukocyte‐Derived High‐Mobility Group Box 1 Governs Hepatic Immune Responses to Listeria monocytogenes

2021 ◽  
Author(s):  
Annika Volmari ◽  
Katharina Foelsch ◽  
Elisabeth Zierz ◽  
Karsten Yan ◽  
Minyue Qi ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Immune Responses ◽  
High Mobility ◽  
High Mobility Group

scholarly journals Leukocyte-derived High-mobility group box 1 controls innate immune responses against Listeria monocytogenes

2019 ◽  
Author(s):  
Annika Volmari ◽  
Katharina Foelsch ◽  
Karsten Yan ◽  
Minyue Qi ◽  
Karlotta Bartels ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Immune Responses ◽  
Tissue Injury ◽  
Myeloid Cells ◽  
High Mobility ◽  
Severe Infection ◽  
High Mobility Group ◽  
Inflammatory Monocyte ◽  
Bacterial Dissemination ◽  
Monocyte Recruitment

AbstractHigh-mobility group box 1 (HMGB1) is a damage-associated molecular pattern with key proinflammatory functions following tissue injury. Moreover, HMGB1 neutralization was shown to alleviate LPS-induced shock, suggesting a role for the protein as a master therapeutic target for inflammatory and infectious diseases. Here, we report that HMGB1 neutralization impedes immune responses to Listeria monocytogenes, a wide-spread bacterium with pathogenic relevance for humans and rodents. Using genetic deletion strategies and neutralizing antibodies, we demonstrate that hepatocyte HMGB1, a major driver of post-necrotic inflammation in the liver, is dispensable for pathogen defense during moderately severe infection with listeria. In contrast, antibody-mediated HMGB1 neutralization and HMGB1 deficiency in myeloid cells effectuate rapid and uncontrolled bacterial dissemination in mice despite preserved basic leukocyte functionality and autophagy induction. During overwhelming infection, hepatocyte injury may contribute to increased HMGB1 serum levels and excessive inflammation in the liver, supporting context-dependent roles for HMGB1 from different cellular compartments during infection. We provide mechanistic evidence that HMGB1 from circulating immune cells contributes to the timely induction of hepatic immune regulatory gene networks, early inflammatory monocyte recruitment to the liver and promotion of neutrophil survival, which are mandatory for pathogen control. In summary, our data establish HMGB1 as a critical co-factor in the immunological clearance of listeria, and argue against HMGB1 neutralization as a universal therapeutic strategy for sepsis.Author summaryHigh-mobility group box 1 (HMGB1) is an abundantly expressed nucleoprotein with signaling properties following secretion or release into the extracellular space. Given its central immune-regulatory roles during tissue injury and LPS-induced septic shock, interventions aimed at HMGB1 signaling have been advocated as therapeutic options for various disease conditions. Here, we show that antibody-mediated HMGB1 neutralization interferes with immunological defense against Listeria monocytogenes, a gram-positive bacterium with high pathogenic relevance for rodents and humans, effectuating uncontrolled bacterial growth and inflammation. Using conditional knockout animals, we demonstrate that while leukocyte functionality is preserved in HMGB1-deficient myeloid cells, HMGB1 released in response to Listeria triggers hepatic inflammatory monocyte recruitment and activation of transcriptional immune networks required for the early control of bacterial dissemination. Hepatocyte HMGB1, a key driver of post-necrotic inflammation in the liver, is dispensable for the immune response during moderately severe infection, but likely contributes to excessive hepatitis when infection is uncontrolled and cellular injury is high. We demonstrate a critical and non-redundant role for HMGB1 in the immune-mediated clearance of listeriosis and argue against HMGB1 neutralization as a universal therapeutic option in the context of infection.

scholarly journals Mucosal Immunization with High-Mobility Group Box 1 in Chitosan Enhances DNA Vaccine-Induced Protection against Coxsackievirus B3-Induced Myocarditis

2013 ◽  
Vol 20 (11) ◽  
pp. 1743-1751 ◽  
Author(s):  
Maowei Wang ◽  
Yan Yue ◽  
Chunsheng Dong ◽  
Xiaoyun Li ◽  
Wei Xu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dna Vaccine ◽  
Myocardial Injury ◽  
Flow Cytometric Analysis ◽  
High Mobility ◽  
Coxsackievirus B3 ◽  
High Mobility Group ◽  
Secretory Iga ◽  
Adjuvant Effect ◽  
Local Immunity

ABSTRACTCoxsackievirus B3 (CVB3), a small single-stranded RNA virus, belongs to thePicornaviridaefamily. Its infection is the most common cause of myocarditis, with no vaccine available. Gastrointestinal mucosa is the major entry port for CVB3; therefore, the induction of local immunity in mucosal tissues may help control initial viral infections and alleviate subsequent myocardial injury. Here we evaluated the ability of high-mobility group box 1 (HMGB1) encapsulated in chitosan particles to enhance the mucosal immune responses induced by the CVB3-specific mucosal DNA vaccine chitosan-pVP1. Mice were intranasally coimmunized with 4 doses of chitosan-pHMGB1 and chitosan-pVP1 plasmids, at 2-week intervals, and were challenged with CVB3 4 weeks after the last immunization. Compared with chitosan-pVP1 immunization alone, coimmunization with chitosan-pHMGB1 significantly (P< 0.05) enhanced CVB3-specific fecal secretory IgA levels and promoted mucosal T cell immune responses. In accordance, reduced severity of myocarditis was observed in coimmunized mice, as evidenced by significantly (P< 0.05) reduced viral loads, decreased myocardial injury, and increased survival rates. Flow cytometric analysis indicated that HMGB1 enhanced dendritic cell (DC) recruitment to mesenteric lymph nodes and promoted DC maturation, which might partly account for its mucosal adjuvant effect. This strategy may represent a promising approach to candidate vaccines against CVB3-induced myocarditis.

scholarly journals High-mobility group nucleosome-binding protein 1 acts as an alarmin and is critical for lipopolysaccharide-induced immune responses

2011 ◽  
Vol 209 (1) ◽  
pp. 157-171 ◽  
Author(s):  
De Yang ◽  
Yuri V. Postnikov ◽  
Yana Li ◽  
Poonam Tewary ◽  
Gonzalo de la Rosa ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Specific Antibody ◽  
High Mobility ◽  
T Cell Responses ◽  
High Mobility Group ◽  
Adaptive Immune Responses ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Nucleosome Binding

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.

Injury Resistance in the Setting of Liver Fibrosis Is Accompanied by the Inhibition of High-Mobility Group Box-1 Translocation and Release

2017 ◽  
Vol 36 (2) ◽  
pp. 167-176 ◽  
Author(s):  
Li Bai ◽  
Waishu Jin ◽  
Ming Kong ◽  
Xiaohui Zhang ◽  
Sujun Zheng ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Immune Responses ◽  
High Mobility ◽  
Spontaneous Resolution ◽  
High Mobility Group ◽  
Enzyme Linked Immunosorbent Assay ◽  
Interesting Phenomenon ◽  
Proinflammatory Mediators ◽  
Acute Insult ◽  
Acute Challenge

Background: Injury resistance occurring in the setting of liver fibrosis is an interesting phenomenon not yet well characterized. In the present study, we investigated dynamically the injury resistance against acute challenge using animal models of hepatic fibrosis and spontaneous resolution, and focused on high-mobility group box-1 (HMGB1), an important proinflammatory mediator. Methods: The hepatic damage of control, fibrosis (CCl4, 6 weeks), and regressive mice with or without CCl4 challenge was dynamically observed and compared. The translocation and release of HMGB1 were assessed by immunohistochemical staining and enzyme-linked immunosorbent assay, respectively. The gene expression of proinflammatory mediators was detected by real-time PCR. Results: Our data showed that the fibrotic mice were invulnerable to acute CCl4 insult. The injury resistance diminished along with the resolution of liver fibrosis. Acute insult triggered the translocation and release of HMGB1 in control mice, which were remarkably inhibited in fibrotic mice, even under acute challenge. Nevertheless, regressive mice exhibited obvious translocation upon insult, especially for R12d mice. HMGB1-related proinflammatory immune responses were suppressed in fibrotic mice; however, they were restored in regressive mice upon insult. Conclusion: The injury resistance in the setting of liver fibrosis is accompanied by the inhibition of HMGB1 translocation and release as well as the suppression of HMGB1-related proinflammatory immune responses.

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