Intestinal CD14+ Macrophages Protect CD4+T Cells From Activation-induced Cell Death via Exosomal Membrane TNF in Crohn's Disease
Intestinal CD14+ Macrophages Protect CD4+T Cells From Activation-induced Cell Death via Exosomal Membrane TNF in Crohn's Disease
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在克罗恩病中，肠道 CD14 巨噬细胞通过外泌体膜 TNF 保护 CD4 T 细胞免受激活诱导的细胞死亡。
DOI：
10.1093/ecco-jcc/jjaa083
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发表时间：
2020-11-01
影响因子：
8
通讯作者：
Lan, Ping
中科院分区：
文献类型：
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作者：
Liu, Huashan;Liang, Zhenxing;Lan, Ping
背景和目的：CD4（+）T细胞的持续激活在克罗恩病的发病机理中起重要作用[CD]。在生理条件下，可以通过称为激活诱导的细胞死亡的过程来及时消除活化的T细胞[AICD]，限制T细胞过度激活和预防免疫学破坏。我们询问有缺陷的AICD是否可以解释CD中的CD4（+）T细胞过度激活并研究了基本机制。方法：CD14（+）巨噬细胞[M-PHI] [M-PHI]和CD4（+）T细胞是从肠道组织或对照组和CD患者的周围血液中分离出来的。使用流式细胞仪测量了一个离体评估系统来模拟AICD，并且通过流式细胞仪测量了细胞凋亡。结果：来自CD患者的CD4（+）T细胞未能在EX VIVO系统中接受AICD。具体而言，促炎的1型助手T [Th1]和17型辅助助手T [Th17]细胞，而不是免疫抑制调节t [Treg]细胞在CD中逃避AICD。 CD的肠炎性微环境中的CD14（+）M-PHI通过细胞与细胞的接触无关的方式在CD4（+）T细胞中促进了AICD抗性。从机械上讲，CD14（+）我释放的外泌体表达膜肿瘤坏死因子[TNF]，该因子在CD4（+）T细胞上与TNFR2接合，并触发NF-KAPPA B信号传导，从而引起AICD耐药性。重要的是，临床上适用的抗TNF抗体有效地阻断了外部外膜TNF诱导的CD4（+）T细胞AICD耐药性。结论：CD14（+）M-PHI参与CD发病机理，通过通过释放外骨膜TNF释放AICD耐药性来激活TNF-tnfr2/nf-nf2/nf2/nf2/nf2/nf2/nf-nf2/b。 These results present new insights into CD pathogenesis and extend mechanistic understanding of anti-TNF agents.Proposed model: CD14(+) M-phi in the intestinal microenvironment of CD patients maintain the sustained activation of CD4'T cells through exosomal membraneTNF to induce apoptosis resistance viaTNFR2/NE-kappa B signalling, which could be effectively blocked by clinically applicable anti-TNF代理商。
Background and aims: Sustained activation of CD4(+)T cells plays important roles in the pathogenesis of Crohn's disease [CD]. Under physiologic conditions, activated T cells can be timely eliminated by a process termed activation-induced cell death [AICD], restraining T cell over-activation and preventing immunological destruction. We inquired whether defective AICD might explain CD4(+)T cell over-activation in CD and investigated the underlying mechanisms.Methods: CD14(+) macrophages [M-phi] and CD4(+) T cells were isolated from intestinal tissues or peripheral blood of controls and CD patients. An ex vivo evaluation system was employed to simulate AICD and cell apoptosis was measured by flow cytometry.Results: CD4(+) T cells from CD patients fail to undergo AICD in the ex vivo system. Specifically, proinflammatory type 1 helper T [Th1] and type 17 helper T [Th17] cells, rather than immunosuppressive regulatory T [Treg] cells evade AICD in CD. CD14(+) M-phi in the intestinal inflammatory microenvironment of CD promote AICD resistance in CD4(+)T cells via a cell-to-cell contact-independent manner. Mechanistically, CD14(+) My released exosomes express membrane tumour necrosis factor [TNF] which engages TNFR2 on CD4(+) T cells and triggers NF-kappa B signalling, thereby causing AICD resistance. Importantly, clinically applicable anti-TNF antibodies effectively blocked exosomal membrane TNF-induced CD4(+)T cell AICD resistance.Conclusions: CD14(+) M-phi participate in CD pathogenesis by inducing AICD resistance through release of exosomal membrane TNF to activate the TNFR2/NF-kappa B pathway in CD4(+) T cells. These results present new insights into CD pathogenesis and extend mechanistic understanding of anti-TNF agents.Proposed model: CD14(+) M-phi in the intestinal microenvironment of CD patients maintain the sustained activation of CD4'T cells through exosomal membraneTNF to induce apoptosis resistance viaTNFR2/NE-kappa B signalling, which could be effectively blocked by clinically applicable anti-TNF agents.