Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes
Abstract Background Gasdermin 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...
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2021
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oai:doaj.org-article:85e85314d3ee434fb76113941a98d1d42021-11-21T12:03:41ZGasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes10.1186/s13075-021-02668-81478-6362https://doaj.org/article/85e85314d3ee434fb76113941a98d1d42021-11-01T00:00:00Zhttps://doi.org/10.1186/s13075-021-02668-8https://doaj.org/toc/1478-6362Abstract Background Gasdermin 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. Methods Gsdmd +/+ 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. Results GSDMD 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. Conclusion GSDMD plays a key role in the pathogenesis of PTOA, but not STIA, suggesting that its actions in experimental arthropathy are tissue context-specific.Tong YangKai SunChun WangGaurav SwarnkarSongtao QuanDustin KressJianqiu XiaoYael AlippeHongjun ZhengRobert H BrophyDingjun HaoAudrey McAlindenYousef Abu-AmerJie ShenGabriel MbalavieleBMCarticleGSDMDIL-1InflammasomeInflammationImmune cellsPyroptosisDiseases of the musculoskeletal systemRC925-935ENArthritis Research & Therapy, Vol 23, Iss 1, Pp 1-13 (2021) |
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DOAJ |
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EN |
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GSDMD IL-1 Inflammasome Inflammation Immune cells Pyroptosis Diseases of the musculoskeletal system RC925-935 |
| spellingShingle |
GSDMD IL-1 Inflammasome Inflammation Immune cells Pyroptosis Diseases of the musculoskeletal system RC925-935 Tong Yang Kai Sun Chun Wang Gaurav Swarnkar Songtao Quan Dustin Kress Jianqiu Xiao Yael Alippe Hongjun Zheng Robert H Brophy Dingjun Hao Audrey McAlinden Yousef Abu-Amer Jie Shen Gabriel Mbalaviele Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes |
| description |
Abstract Background Gasdermin 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. Methods Gsdmd +/+ 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. Results GSDMD 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. Conclusion GSDMD plays a key role in the pathogenesis of PTOA, but not STIA, suggesting that its actions in experimental arthropathy are tissue context-specific. |
| format |
article |
| author |
Tong Yang Kai Sun Chun Wang Gaurav Swarnkar Songtao Quan Dustin Kress Jianqiu Xiao Yael Alippe Hongjun Zheng Robert H Brophy Dingjun Hao Audrey McAlinden Yousef Abu-Amer Jie Shen Gabriel Mbalaviele |
| author_facet |
Tong Yang Kai Sun Chun Wang Gaurav Swarnkar Songtao Quan Dustin Kress Jianqiu Xiao Yael Alippe Hongjun Zheng Robert H Brophy Dingjun Hao Audrey McAlinden Yousef Abu-Amer Jie Shen Gabriel Mbalaviele |
| author_sort |
Tong Yang |
| title |
Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes |
| title_short |
Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes |
| title_full |
Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes |
| title_fullStr |
Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes |
| title_full_unstemmed |
Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes |
| title_sort |
gasdermin d deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/85e85314d3ee434fb76113941a98d1d4 |
| work_keys_str_mv |
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