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Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases.

ABSTRACT: Heat shock proteins have been implicated as endogenous activators for dendritic cells (DCs). Without tissue distress or death, these intracellular molecules are inaccessible to surface receptor(s) on DCs, possibly to avoid uncontrolled DC activation and breakdown of immunologic tolerance. We herein addressed this hypothesis in transgenic mice by enforcing cell surface expression of gp96, a ubiquitous heat shock protein of the endoplasmic reticulum. Although a pan-specific promoter is used for transgene expression, neither the expression level nor the tissue distribution of the endogenous gp96 was altered by this maneuver. However, cell surface gp96 induced significant DC activations and spontaneous lupus-like autoimmune diseases, even though the development/functions of lymphocytic compartments were unaltered. Using a bone marrow chimera approach, we further demonstrated that both DC activation and autoimmunity elicited by cell surface gp96 are dependent on the downstream adaptor protein MyD88 for signaling by Toll/IL-1 receptor family. Our study not only established the proinflammatory property of cell surface gp96 in vivo, but also suggested a chronic stimulation of DCs by gp96 as a pathway to initiate spontaneous autoimmune diseases.

SUBMITTER: Liu B

PROVIDER: S-EPMC307652 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature

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Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases.

Liu Bei B Dai Jie J Zheng Hong H Stoilova Diliana D Sun Shaoli S Li Zihai Z

Proceedings of the National Academy of Sciences of the United States of America 20031210 26

Heat shock proteins have been implicated as endogenous activators for dendritic cells (DCs). Without tissue distress or death, these intracellular molecules are inaccessible to surface receptor(s) on DCs, possibly to avoid uncontrolled DC activation and breakdown of immunologic tolerance. We herein addressed this hypothesis in transgenic mice by enforcing cell surface expression of gp96, a ubiquitous heat shock protein of the endoplasmic reticulum. Although a pan-specific promoter is used for tr ...[more]

PMID: 14668429

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Project description:Cellular stress-mediated chaperones are linked to liver macrophage activation and inflammation in alcohol-associated liver disease (ALD). In this study, we investigate the role of endoplasmic reticulum (ER) resident stress chaperone GP96/HSP90B1/GRP94, paralog of the HSP90 family, in ALD pathogenesis. We hypothesize that ER resident chaperone, heat shock protein GP96, plays a crucial role in alcohol-associated liver inflammation and contributes to liver injury. We show high expression of GP96/HSP90B1 and GRP78/HSPA5 in human alcohol-associated hepatitis livers as well as in mouse ALD livers with induction of GP96 prominent in alcohol-exposed macrophages. Myeloid-specific GP96 deficient (M-GP96KO) mice failed to induce alcohol-associated liver injury. Alcohol-fed M-GP96KO mice exhibit significant reduction in steatosis, serum endotoxin, and pro-inflammatory cytokines compared with wild-type mice. Anti-inflammatory cytokines interleukin-10 and transforming growth factor β, as well as activating transcription factor 3 and triggering receptor expressed on myeloid cells 2, markers of restorative macrophages, were higher in alcohol-fed M-GP96KO livers. M-GP96KO mice exhibit protection in a model of endotoxin-mediated liver injury in vivo, which is in agreement with reduced inflammatory responses during ex vivo lipopolysaccharide/endotoxin- stimulated bone marrow-derived macrophages from M-GP96KO mice. Furthermore, we show that liver macrophages from alcohol-fed M-GP96KO mice show compensatory induction of GRP78 messenger RNA, likely due to increased splicing of X-box binding protein-1. Finally, we show that inhibition of GP96 using a specific pharmacological agent, PU-WS13 or small interfering RNA, alleviates inflammatory responses in primary macrophages. Conclusion: Myeloid ER resident GP96 promotes alcohol-induced liver damage through activation of liver macrophage inflammatory responses, alteration in lipid homeostasis, and ER stress. These findings highlight a critical role for liver macrophage ER resident chaperone GP96/HSP90B1 in ALD, and its targeted inhibition represents a promising therapeutic approach in ALD.

Dataset Information

Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases.

Publications

Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases.

Similar Datasets

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