Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Australia.
Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Australia.
Dev Cell. 2023 Nov 6;58(21):2235-2248.e6. doi: 10.1016/j.devcel.2023.08.009. Epub 2023 Aug 29.
Apoptosis is traditionally considered to be an immunologically silent form of cell death. Multiple mechanisms exist to ensure that apoptosis does not stimulate the immune system to cause inflammation or autoimmunity. Against this expectation, we now report that epithelia are programmed to provoke, rather than suppress, inflammation in response to apoptosis. We found that an acute inflammatory response led by neutrophils occurs in zebrafish and cell culture when apoptotic epithelial cells cannot be expelled from the monolayer by apical extrusion. This reflects an intrinsic circuit where ATP released from apoptotic cells stimulates epithelial cells in the immediate vicinity to produce interleukin-8 (IL-8). Apical extrusion therefore prevents inappropriate epithelial inflammation by physically eliminating apoptotic cells before they can activate this pro-inflammatory circuit. This carries the implication that epithelia may be predisposed to inflammation, elicited by sporadic or induced apoptosis, if apical extrusion is compromised.
细胞凋亡通常被认为是一种免疫沉默的细胞死亡形式。存在多种机制来确保细胞凋亡不会刺激免疫系统引起炎症或自身免疫。与这种预期相反，我们现在报告称，上皮细胞被编程为在细胞凋亡时引发炎症，而不是抑制炎症。我们发现，当上皮细胞不能通过顶端挤出而从单层中排出时，在斑马鱼和细胞培养物中，中性粒细胞介导的急性炎症反应会发生。这反映了一个内在的回路，即凋亡细胞释放的 ATP 会刺激附近的上皮细胞产生白细胞介素-8 (IL-8)。因此，顶端挤出通过在凋亡细胞激活这种促炎回路之前将其物理清除，从而防止上皮细胞的不适当炎症。这意味着，如果顶端挤出受损，上皮细胞可能会因偶发性或诱导的细胞凋亡而容易引发炎症。
