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

Arthritis Research & Therapy

Gaurav Swarnkar¹  Jie Shen¹  Hongjun Zheng¹  Robert H Brophy¹  Yousef Abu-Amer²  Audrey McAlinden²  Yael Alippe³  Dustin Kress³  Jianqiu Xiao³  Gabriel Mbalaviele³  Chun Wang³  Songtao Quan⁴  Dingjun Hao⁵  Kai Sun⁶  Tong Yang⁶ 

[1] Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA;Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA;Shriners Hospital for Children, St. Louis, MO, USA;Division of Bone and Mineral Diseases, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8301, 63110, St. Louis, MO, USA;Luoyang Orthopedic - Traumatological Hospital of Henan Province, Luoyang, Henan, China;Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China;Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China;Division of Bone and Mineral Diseases, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8301, 63110, St. Louis, MO, USA;

关键词: GSDMD;    IL-1;    Inflammasome;    Inflammation;    Immune cells;    Pyroptosis;    Bone;    Arthritis;   

DOI  :  10.1186/s13075-021-02668-8

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY