Induction of ASC pyroptosis requires gasdermin D or caspase-1/11-dependent mediators and IFNβ from pyroptotic macrophages
Induction of ASC pyroptosis requires gasdermin D or caspase-1/11-dependent mediators and IFNβ from pyroptotic macrophages
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ASC 焦亡的诱导需要gasdermin D 或caspase-1/11 依赖性介质和来自焦亡巨噬细胞的IFNβ
DOI：
10.1038/s41419-020-2664-0
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发表时间：
2020
影响因子：
9
通讯作者：
Xiao Su
中科院分区：
文献类型：
--
作者：
Cuiping Zhang;Caiqi Zhao;Xiaoyan Chen;Rujia Tao;Sijiao Wang;Guangxun Meng;Xing Liu;Changzhou Shao;Xiao Su
间充质干细胞（MSCs）已被用于多种疾病的细胞治疗。病变部位的炎症介质等因素可能会损害MSCs的存活，影响其疗效。焦亡是程序性坏死的一种形式，是免疫细胞对细胞质致病性刺激的反应。MSCs是否在病理刺激下发生焦亡，其潜在机制和生物学意义尚不清楚。在这里，我们发现LPS、鞭毛蛋白、dsDNA、尼日利亚菌素（NIG）或LPS联合尼日利亚菌素（LPS/NIG）不能诱导脂肪组织源性间充质干细胞（ASCs）的焦亡。然而，当将LPS/ nig诱导的热噬骨髓源性巨噬细胞（bmdm）的培养基用于培养ASCs时，ASCs发生了焦亡。在ASCs中抑制caspase或缺失caspase -1/11不影响巨噬细胞介质引发的ASC焦亡，而消融caspase -1/11可消除LPS/NIG诱导的BMDM焦亡。LPS/NIG刺激gsdmd−/−或caspase -1/11−/−BMDMs收集的培养基不能诱导ASCs焦亡。此外，RNA-seq分析显示，干扰素（IFN）刺激基因在焦腐性ASCs中表达上调。添加IFNβ可促进LPS/NIG刺激的BMDM介质诱导的ASC焦亡。令人惊讶的是，热腐ASCs具有较低的杀菌能力。绿脓杆菌。综上所述，诱导ASC焦亡需要来自焦亡巨噬细胞的gasdermin D或caspase-1/11依赖性介质和IFNβ。
Mesenchymal stem cells (MSCs) have been used in cell-based therapies for a variety of disorders. Some factors such as inflammatory mediators in the diseased area might damage the survival of MSCs and affect their efficacy. Pyroptosis is a form of programmed necrosis as a response for immune cells to cytosolic pathogenic stimuli. Whether MSCs develop pyroptosis under pathological stimulation, its underlying mechanism and biological significance are still unclear. Here, we found that LPS, flagellin, dsDNA, nigericin (NIG), or LPS combined with nigericin (LPS/NIG) could not induce pyroptosis in adipose-tissue-derived mesenchymal stem cells (ASCs). However, when applied the culture media collected from LPS/NIG-induced pyroptotic bone marrow-derived macrophages (BMDMs) to incubate ASCs, ASCs developed pyroptosis. Inhibition of caspases or deletion ofCaspase-1/11in ASCs did not affect the pyroptotic macrophage media-triggered ASC pyroptosis while ablation ofCaspase-1/11abolished BMDM pyroptosis induced by LPS/NIG. Media collected from LPS/NIG stimulatedGsdmd−/−orCaspase-1/11−/−BMDMs could not induce pyroptosis of ASCs. In addition, RNA-seq analysis showed that interferon (IFN)-stimulated genes were upregulated in pyroptotic ASCs. Adding IFNβ could boost LPS/NIG stimulated BMDM media-induced ASC pyroptosis. Surprisingly, the pyroptotic ASCs had a lower bactericidal ability toP. Aeruginosa. Taken together, induction of ASC pyroptosis requires gasdermin D or caspase-1/11-dependent mediators and IFNβ from pyroptotic macrophages.