Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis.
Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis.
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DOI：
10.1038/s41598-021-98145-y
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发表时间：
2021-09-21
影响因子：
4.6
通讯作者：
Hirota K
中科院分区：
文献类型：
--
作者：
Takeuchi Y;Ohara D;Watanabe H;Sakaguchi N;Sakaguchi S;Kondoh G;Morinobu A;Mimori T;Hirota K
程序性坏死，如坏死性凋亡和焦亡，是一种与慢性炎症相关的高度促炎性细胞事件。尽管在自身免疫性组织炎症中存在多种引起细胞凋亡和坏死的触发因素，并且随后的细胞死亡的裂解形式释放大量的炎性介质，包括损伤相关分子模式和IL-1β，能够放大自身免疫性Th 17效应器功能，但这些程序是否在自身免疫性关节炎的发病机制中起关键作用仍然很不清楚。我们在此报道Gasdermin D（Gsdmd）和受体相互作用丝氨酸/苏氨酸激酶3（Ripk 3）--分别是细胞凋亡和坏死凋亡的关键分子--在SKG小鼠炎症滑膜组织中上调，但抑制IL-1β的产生和产生IL-17的辅助性T细胞（Th 17）介导的自身免疫性关节炎的发展。Gsdmd−/−、Ripk 3 −/−或Gsdmd−/− Ripk 3 −/− SKG小鼠表现出严重的关节炎，引流LN和炎症关节中致关节炎Th 17细胞扩增，与野生型SKG小鼠相当。尽管经典刺激显著降低了Gsdmd−/−或Ripk 3 −/−骨髓来源DC的IL-1β分泌，但在Gsdmd或Ripk 3缺失的情况下，炎症滑膜中的IL-1β水平不受影响。我们的研究结果表明，T细胞介导的自身免疫性关节炎的进展独立的细胞凋亡和坏死凋亡途径。
Programmed necrosis, such as necroptosis and pyroptosis, is a highly pro-inflammatory cellular event that is associated with chronic inflammation. Although there are various triggers of pyroptosis and necroptosis in autoimmune tissue inflammation and subsequent lytic forms of cell death release abundant inflammatory mediators, including damage-associated molecular patterns and IL-1β, capable of amplifying autoimmune Th17 effector functions, it remains largely unclear whether the programs play a crucial role in the pathogenesis of autoimmune arthritis. We herein report that Gasdermin D (Gsdmd) and receptor interacting serine/threonine kinase 3 (Ripk3)—key molecules of pyroptosis and necroptosis, respectively—are upregulated in inflamed synovial tissues, but dispensable for IL-1β production and the development of IL-17-producing T helper (Th17) cell-mediated autoimmune arthritis in SKG mice. Gsdmd−/−, Ripk3−/−, or Gsdmd−/− Ripk3−/− SKG mice showed severe arthritis with expansion of arthritogenic Th17 cells in the draining LNs and inflamed joints, which was comparable to that in wild-type SKG mice. Despite the marked reduction of IL-1β secretion from Gsdmd−/− or Ripk3−/− bone marrow-derived DCs by canonical stimuli, IL-1β levels in the inflamed synovium were not affected in the absence of Gsdmd or Ripk3. Our results revealed that T cell-mediated autoimmune arthritis proceeds independently of the pyroptosis and necroptosis pathways.
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4.6
作者：
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通讯作者：
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影响因子：
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作者：
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CaMKII 是一种 RIP3 底物，介导缺血和氧化应激诱导的心肌坏死性凋亡。
影响因子：
82.9
作者：
Zhang, Ting;Zhang, Yan;Xiao, Rui-Ping
通讯作者：
Xiao, Rui-Ping