The Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK.
Centre for Physiopathology Toulouse-Purpan, INSERM U1043, CNRS U5282, Toulouse University, Toulouse, France.
Cell Death Dis. 2021 Mar 19;12(4):296. doi: 10.1038/s41419-021-03528-8.
Persistent neutrophilic inflammation drives host damage in autoimmune diseases that are characterized by abundant immune complexes. Insoluble immune complexes (iICs) potently activate pro-inflammatory neutrophil effector functions. We and others have shown that iICs also promote resolution of inflammation via stimulation of neutrophil apoptosis. We demonstrate here that iICs trigger FcγRIIa-dependent neutrophil macropinocytosis, leading to the rapid uptake, and subsequent degradation of iICs. We provide evidence that concurrent iIC-induced neutrophil apoptosis is distinct from phagocytosis-induced cell death. First, uptake of iICs occurs by FcγRII-stimulated macropinocytosis, rather than phagocytosis. Second, production of reactive oxygen species, but not iIC-internalization is a pre-requisite for iIC-induced neutrophil apoptosis. Our findings identify a previously unknown mechanism by which neutrophils can remove pro-inflammatory iICs from the circulation. Together iIC clearance and iIC-induced neutrophil apoptosis may act to prevent the potential escalation of neutrophilic inflammation in response to iICs.
持续的中性粒细胞炎症会导致自身免疫性疾病的宿主损伤，这些疾病的特点是存在大量免疫复合物。不溶性免疫复合物（iICs）能强烈激活促炎中性粒细胞效应功能。我们和其他人已经表明，iICs 还通过刺激中性粒细胞凋亡来促进炎症的消退。我们在这里证明，iICs 触发 FcγRIIa 依赖性中性粒细胞巨胞饮作用，导致 iICs 的快速摄取和随后的降解。我们提供的证据表明，同时发生的 iIC 诱导的中性粒细胞凋亡与吞噬作用诱导的细胞死亡不同。首先，iIC 的摄取是通过 FcγRII 刺激的巨胞饮作用，而不是吞噬作用。其次，活性氧的产生，而不是 iIC 的内化，是 iIC 诱导的中性粒细胞凋亡的先决条件。我们的发现确定了一种以前未知的机制，即中性粒细胞可以从循环中清除促炎的 iICs。总的来说，iIC 的清除和 iIC 诱导的中性粒细胞凋亡可能有助于防止针对 iICs 的中性粒细胞炎症的潜在升级。
