HMGB1-TLR4-MyD88 Axis Exacerbates Experimental Viral Fulminant Hepatitis
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- 英文论文题名：HMGB1-TLR4-MyD88 Axis Exacerbates Experimental Viral Fulminant Hepatitis
- 论文作者：Diao Bo ; Yang Chengying ; Fei Lei ; Guo Sheng ; Zhang Ji ; Wu Yuzhang ; Chen Yongwen
- 英文论文作者：Diao Bo ; Yang Chengying ; Fei Lei ; Guo Sheng ; Zhang Ji ; Wu Yuzhang ; Chen Yongwen ; Institute of Immunology ; PLA ; Third Military Medical University
- 年：2016
- 作者机构：Institute of Immunology,PLA,Third Military Medical University;
- 英文论文关键词：MHV-3 ; viral infection ; fulminant hepatitis ; Myd88 ; HMGB1
- 会议召开时间：2016-11-04
- 会议录名称：第十一届全国免疫学学术大会摘要汇编
- 英文会议录名称：Abstracts of 2016 CSI Congress on Immunology
- 语种：英文
- 分类号：R512.6
- 学会代码：IGMD
- 会议名称：第十一届全国免疫学学术大会
- 会议地点：中国安徽合肥
- 主办单位：中国免疫学会
- 学会名称：中国免疫学会
- 页数：1
- 文件大小：380k
- 原文格式：D
- 会议级别：全国
摘要
Aim: Viral fulminant hepatitis(FH) is a serious liver disease with high mortality due to excessive inflammation in liver tissues. The lack of knowledge on inflammatory signal dysregulation attributing to FH pathogenesis has been an obstacle for seeking effective interventions.Methods: Mice were injected with MHV-3 via i.p. In some experiments, the virus infected mice were treated with HMGB1 blocking m Abs. Mice were euthanized on the indicated days and the virus titers in liver were determined by plaque assay. Serum FGL2, IL-17, TNF-α, C5 a, IL-1β and HMGB1 levels were measured by ELISA. The expression of HMGB1, FGL2, TNF-α and IL-6 in MHV-3 infected livers was detected by Western-blotting.Results: We report that mice deficiency in My D88(My D88-/-), an adaptor protein that mediates Toll-like receptor(TLR), IL-1R and IL-18 R signaling, are resistant to murine hepatitis virus strain-3(MHV-3)-mediated FH. The expression of multiple pro-inflammatory cytokines and chemokines causing the recruitment of inflammatory macrophages, which produce IL-17, TNF-α and IL-1β, to the livers was severely impaired in My D88-/- mice as compared to wild-type(WT) littermates, resulting in reduced liver pathology, viral replication and prolonged mortality post-infection. The liver infiltration of macrophages was mediated by CXCR5 at a very early time of infection, and CXCR5-/-mice phenocopied My D88-/- mice and exhibited reduced liver damage against MHV-3 infection. Additionally, MHV-3 markedly augments expression of high-mobility group box 1(HMGB1) in infected hepatocytes/macrophages and induces HMGB1 protein migration from the nucleus to the extracellular milieu, where it activates My D88-dependent inflammation by binding to TLR4 receptor. Conversely, TLR4-/- mice or WT animals treated with the HMGB1 blocking antibodies are resistant to MHV-3-caused FH. Conclusion: These results demonstrate that the HMGB1-TLR4-My D88 axis is essential in controlling the pathogenesis of viral FH, and interruption of this signaling pathway sheds light on a novel therapeutic strategy for the disease.
Aim: Viral fulminant hepatitis(FH) is a serious liver disease with high mortality due to excessive inflammation in liver tissues. The lack of knowledge on inflammatory signal dysregulation attributing to FH pathogenesis has been an obstacle for seeking effective interventions.Methods: Mice were injected with MHV-3 via i.p. In some experiments, the virus infected mice were treated with HMGB1 blocking m Abs. Mice were euthanized on the indicated days and the virus titers in liver were determined by plaque assay. Serum FGL2, IL-17, TNF-α, C5 a, IL-1β and HMGB1 levels were measured by ELISA. The expression of HMGB1, FGL2, TNF-α and IL-6 in MHV-3 infected livers was detected by Western-blotting.Results: We report that mice deficiency in My D88(MyD88~(-/-)), an adaptor protein that mediates Toll-like receptor(TLR), IL-1R and IL-18 R signaling, are resistant to murine hepatitis virus strain-3(MHV-3)-mediated FH. The expression of multiple pro-inflammatory cytokines and chemokines causing the recruitment of inflammatory macrophages, which produce IL-17, TNF-α and IL-1β, to the livers was severely impaired in My D88~(-/-) mice as compared to wild-type(WT) littermates, resulting in reduced liver pathology, viral replication and prolonged mortality post-infection. The liver infiltration of macrophages was mediated by CXCR5 at a very early time of infection, and CXCR5-/-mice phenocopied My D88~(-/-) mice and exhibited reduced liver damage against MHV-3 infection. Additionally, MHV-3 markedly augments expression of high-mobility group box 1(HMGB1) in infected hepatocytes/macrophages and induces HMGB1 protein migration from the nucleus to the extracellular milieu, where it activates My D88-dependent inflammation by binding to TLR4 receptor. Conversely, TLR4~(-/-) mice or WT animals treated with the HMGB1 blocking antibodies are resistant to MHV-3-caused FH. Conclusion: These results demonstrate that the HMGB1-TLR4-My D88 axis is essential in controlling the pathogenesis of viral FH, and interruption of this signaling pathway sheds light on a novel therapeutic strategy for the disease.
Aim: Viral fulminant hepatitis(FH) is a serious liver disease with high mortality due to excessive inflammation in liver tissues. The lack of knowledge on inflammatory signal dysregulation attributing to FH pathogenesis has been an obstacle for seeking effective interventions.Methods: Mice were injected with MHV-3 via i.p. In some experiments, the virus infected mice were treated with HMGB1 blocking m Abs. Mice were euthanized on the indicated days and the virus titers in liver were determined by plaque assay. Serum FGL2, IL-17, TNF-α, C5 a, IL-1β and HMGB1 levels were measured by ELISA. The expression of HMGB1, FGL2, TNF-α and IL-6 in MHV-3 infected livers was detected by Western-blotting.Results: We report that mice deficiency in My D88(MyD88~(-/-)), an adaptor protein that mediates Toll-like receptor(TLR), IL-1R and IL-18 R signaling, are resistant to murine hepatitis virus strain-3(MHV-3)-mediated FH. The expression of multiple pro-inflammatory cytokines and chemokines causing the recruitment of inflammatory macrophages, which produce IL-17, TNF-α and IL-1β, to the livers was severely impaired in My D88~(-/-) mice as compared to wild-type(WT) littermates, resulting in reduced liver pathology, viral replication and prolonged mortality post-infection. The liver infiltration of macrophages was mediated by CXCR5 at a very early time of infection, and CXCR5-/-mice phenocopied My D88~(-/-) mice and exhibited reduced liver damage against MHV-3 infection. Additionally, MHV-3 markedly augments expression of high-mobility group box 1(HMGB1) in infected hepatocytes/macrophages and induces HMGB1 protein migration from the nucleus to the extracellular milieu, where it activates My D88-dependent inflammation by binding to TLR4 receptor. Conversely, TLR4~(-/-) mice or WT animals treated with the HMGB1 blocking antibodies are resistant to MHV-3-caused FH. Conclusion: These results demonstrate that the HMGB1-TLR4-My D88 axis is essential in controlling the pathogenesis of viral FH, and interruption of this signaling pathway sheds light on a novel therapeutic strategy for the disease.
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