Serum Gp96 is a chaperone of complement-C3 during graft-versus-host disease

Seignez, Antoine; Joly, Anne-Laure; Chaumonnot, Killian; Hazoumé, Adonis; Sanka, Michel; Marcion, Guillaume; Boudesco, Christophe; Hammann, Arlette; Seigneuric, Renaud; Jégo, Gaëtan; Ducoroy, Patrick; Delarue, Patrice; Senet, Patrick; Castilla‐Llorente, Cristina; Solary, Éric; Durey, Marie-Agnès; Rubio, Marie‐Thérèse; Hermine, Olivier; Kohli, Évelyne; Garrido, Carmen

doi:10.1172/jci.insight.90531

Cited by 11 publications

(13 citation statements)

References 35 publications

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“…Published imaging studies confirm that corneal nerve remodeling occurs in patients with ocular GVHD (He et al, 2017a; Tepelus et al, 2017); therefore, clinical studies to delineate the kinetics of disease onset are needed. Complement C3 is a known driver of systemic GVHD (Kwan et al, 2012; Ma et al, 2014; Seignez et al, 2017), and our data show that aberrant complement pathway activation also contributes to the pathogenesis of ocular GVHD including corneal sensation loss. Furthermore, localized CVF treatment preserved corneal sensation in both sexes during ocular GVHD, but treatment only abrogated other facets of ocular surface disease in female mice.…”

Section: Discussionmentioning

confidence: 56%

Complement and CD4+ T cells drive context-specific corneal sensory neuropathy

Royer

Echegaray-Mendez

Lin

et al. 2019

eLife

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Whether complement dysregulation directly contributes to the pathogenesis of peripheral nervous system diseases, including sensory neuropathies, is unclear. We addressed this important question in a mouse model of ocular HSV-1 infection, where sensory nerve damage is a common clinical problem. Through genetic and pharmacologic targeting, we uncovered a central role for C3 in sensory nerve damage at the morphological and functional levels. Interestingly, CD4 T cells were central in facilitating this complement-mediated damage. This same C3/CD4 T cell axis triggered corneal sensory nerve damage in a mouse model of ocular graft-versus-host disease (GVHD). However, this was not the case in a T-dependent allergic eye disease (AED) model, suggesting that this inflammatory neuroimmune pathology is specific to certain disease etiologies. Collectively, these findings uncover a central role for complement in CD4 T cell-dependent corneal nerve damage in multiple disease settings and indicate the possibility for complement-targeted therapeutics to mitigate sensory neuropathies.

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Section: Discussionmentioning

confidence: 56%

Complement and CD4+ T cells drive context-specific corneal sensory neuropathy

Royer

Echegaray-Mendez

Lin

et al. 2019

eLife

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“…Based on these results and on our previous results showing that extracellular GRP94 interacts with the complement C3 4 , we decided to study the intracellular interaction GRP94-C3 in macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…To better understand GRP94 role in macrophages, we analyzed intracellular and cell surface expression of GRP94 in M1 and M2 macrophages derived from PBMC of healthy volunteers, at basal and ER stress conditions. Moreover, as we previously showed that extracellular GRP94 associates with the complement C3 4 and Liszewski et al have reported that shuttling of the intracellular C3-activation-system to the cell surface upon T cell stimulation induces autocrine pro-inflammatory cytokine production 18 , we analyzed the interaction GRP94-C3 in macrophages and studied its potential role in their polarization.…”

Section: Introductionmentioning

confidence: 96%

“…Glucose-regulated protein 94 (GRP94, also known as Gp96) is an endoplasmic reticulum (ER) member of the heat shock protein HSP90 family whose expression is increased during ER stress 1 . GRP94 has also been reported in physiological or pathological situations in the extracellular medium [2][3][4] and at the surface of tumor cells (reviewed in ref. 5 ).…”

Section: Introductionmentioning

confidence: 99%

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The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress

et al. 2021

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The role of GRP94, an endoplasmic reticulum (ER) stress protein with both pro- and anti-inflammatory functions, has not been investigated in macrophages during ER stress, whereas ER stress has been reported in many diseases involving macrophages. In this work, we studied GRP94 in M1/LPS + IFNγ and M2/IL-4 primary macrophages derived from human monocytes (isolated from buffy coats), in basal and ER stress conditions induced by thapsigargin (Tg), an inducer of ER calcium depletion and tunicamycin (Tm), an inhibitor of N-glycosylation. We found that GRP94 was expressed on the membrane of M2 but not M1 macrophages. In M2, Tg, but not Tm, while decreased GRP94 content in the membrane, it induced its secretion. This correlated with the induction of a pro-inflammatory profile, which was dependent on the UPR IRE1α arm activation and on a functional GRP94. As we previously reported that GRP94 associated with complement C3 at the extracellular level, we analyzed C3 and confirmed GRP94-C3 interaction in our experimental model. Further, Tg increased this interaction and, in these conditions, C3b and cathepsin L were detected in the extracellular medium where GRP94 co-immunoprecipitated with C3 and C3b. Finally, we showed that the C3b inactivated fragment, iC3b, only present on non-stressed M2, depended on functional GRP94, making both GRP94 and iC3b potential markers of M2 cells. In conclusion, our results show that GRP94 is co-secreted with C3 under ER stress conditions which may facilitate its cleavage by cathepsin L, thus contributing to the pro-inflammatory profile observed in stressed M2 macrophages.

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“…Pope et al discovered that high levels of gp96-IgG complexes exist in the synovial fluids of patients with rheumatoid arthritis (RA), and these gp96 molecules can activate macrophages to secrete inflammatory cytokines such as IL-6 and TNF-α 23 . Patients with type 1 diabetes 24 or with gastrointestinal graft-versus-host disease (GVHD) 25 exhibit high levels of circulating gp96, and gp96 levels correlate with disease severity, supporting the notion that extracellular gp96 is involved in autoimmune conditions. Additionally, Lewis et al found that exogenous gp96 leads to the activation of immune cells in vivo, which in turn leads to the reduction of survival time of mice with pancreatic islet transplantation 26 .…”

mentioning

confidence: 95%

Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage

Guan

Ding²,

Liu³

et al. 2020

Sci Rep

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Liver failure leads to the massive necrosis of hepatocytes, releasing large amounts of intracellular components including damage-associated molecular patterns (DAMPs). We found that extracellular gp96 levels in serum were elevated in patients with chronic hepatitis B infection (CHB) and acuteon-chronic liver failure (ACLF). Meanwhile, the gp96 level positively correlated with hepatic necroinflammation. We employed two mouse liver damage and liver failure models induced by lipopolysaccharide (LPS) plus d-galactosamine (d-Galn), and concanavalin A (ConA) to identify the function of extracellular gp96. As a result, the inhibition of extracellular gp96 by a specific peptide efficiently mitigated both LPS/d-Galn-and ConA-induced liver injury and immune hyperactivation, whereas exogenous gp96 aggravated the symptoms of hepatic injury in mice but not in Kupffer cells-ablated mice. The exposure of Kupffer cells to gp96 induced the secretion of pro-inflammatory cytokines. Collectively, our data demonstrate that gp96 released from necrotic hepatocytes aggravates immune hyperactivation and promotes liver damage and possibly the development of liver failure mainly by activating Kupffer cells.

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Serum Gp96 is a chaperone of complement-C3 during graft-versus-host disease

Cited by 11 publications

References 35 publications

Complement and CD4+ T cells drive context-specific corneal sensory neuropathy

Complement and CD4+ T cells drive context-specific corneal sensory neuropathy

The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress

Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage

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