Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes

Tong Yang,Gaurav Swarnkar,Yousef Abu-Amer,Audrey Mcalinden,Jianqiu Xiao,Jie Shen,Dingjun Hao,Robert H Brophy,Hongjun Zheng,Yael Alippe,Dustin Kress,Kai Sun,Gabriel Mbalaviele,Songtao Quan,Chun Wang

doi:10.1186/s13075-021-02668-8

Abstract

BackgroundGasdermin D (GSDMD) is cleaved by several proteases including by caspase-1, a component of intracellular protein complexes called inflammasomes. Caspase-1 also converts pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into bioactive IL-1β and IL-18, respectively. GSDMD amino-terminal fragments form plasma membrane pores, which mediate the secretion of IL-1β and IL-18 and cause the inflammatory form of cell death pyroptosis. Here, we tested the hypothesis that GSDMD contributes to joint degeneration in the K/BxN serum transfer-induced arthritis (STIA) model in which autoantibodies against glucose-6-phosphate isomerase promote the formation of pathogenic immune complexes on the surface of myeloid cells, which highly express the inflammasomes. The unexpected outcomes with the STIA model prompted us to determine the role of GSDMD in the post-traumatic osteoarthritis (PTOA) model caused by meniscus ligamentous injury (MLI) based on the hypothesis that this pore-forming protein is activated by signals released from damaged joint tissues.MethodsGsdmd+/+ and Gsdmd−/− mice were injected with K/BxN mouse serum or subjected to MLI to cause STIA or PTOA, respectively. Paw and ankle swelling and DXA scanning were used to assess the outcomes in the STIA model whereas histopathology and micro-computed tomography (μCT) were utilized to monitor joints in the PTOA model. Murine and human joint tissues were also examined for GSDMD, IL-1β, and IL-18 expression by qPCR, immunohistochemistry, or immunoblotting.ResultsGSDMD levels were higher in serum-inoculated paws compared to PBS-injected paws. Unexpectedly, ablation of GSDMD failed to reduce joint swelling and osteolysis, suggesting that GSDMD was dispensable for the pathogenesis of STIA. GSDMD levels were also higher in MLI compared to sham-operated joints. Importantly, ablation of GSDMD attenuated MLI-associated cartilage degradation (p = 0.0097), synovitis (p = 0.014), subchondral bone sclerosis (p = 0.0006), and subchondral bone plate thickness (p = 0.0174) based on histopathological and μCT analyses.ConclusionGSDMD plays a key role in the pathogenesis of PTOA, but not STIA, suggesting that its actions in experimental arthropathy are tissue context-specific.

Highlights

Gasdermin D (GSDMD) is cleaved by several proteases including by caspase-1, a component of intra‐ cellular protein complexes called inflammasomes
GSDMD deficiency failed to reduce joint swelling and osteolysis in the STIA model The serum of K/BxN mice contains autoantibodies against glucose-6-phosphate isomerase (G6PI), which upon transfer to recipient animals consistently cause inflammatory arthritis [37]. This model commonly referred to as serum transfer-induced arthritis (STIA) reproduces the effector phase of rheumatoid arthritis (RA) as G6PI autoantibodies promote the formation of immune complexes that activate innate immune cells such as neutrophils and macrophages
These results suggest that GSDMD does not play a key role in the pathogenesis of STIA

Summary

Introduction

Gasdermin D (GSDMD) is cleaved by several proteases including by caspase-1, a component of intra‐ cellular protein complexes called inflammasomes. The unexpected outcomes with the STIA model prompted us to determine the role of GSDMD in the post-traumatic osteoarthritis (PTOA) model caused by meniscus ligamentous injury (MLI) based on the hypothesis that this pore-forming protein is activated by signals released from damaged joint tissues. The etiology of RA remains unclear, its progression is associated with dysregulated inflammatory actions of various cell types including macrophages, neutrophils, T cells, B cells, and synovial fibroblasts [2,3,4,5,6] These responses take place within the synovium and lead to the formation of the pannus, a tumor-like structure, which invades and damages the cartilage and bone [7, 8]. Certain patients are refractory to current cytokine-based therapies, and in spite of the pivotal role of IL-1β in maintaining synovitis and inducing bone erosion, IL-1 blockade shows limited efficacy in improving clinical symptoms of RA patients [15]

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Conclusion