ARTS (Sept4_i2) is a pro-apoptotic protein and a product of the Sept4 gene. ARTS acts upstream of mitochondria to initiate caspase activation. ARTS induces apoptosis by specifically binding XIAP and allowing de-repression of active caspases required for Mitochondrial Outer Membrane Permeabilzation (MOMP). Moreover, ARTS promotes apoptosis by inducing ubiquitin-mediated degradation of both major anti-apoptotic proteins XIAP and Bcl-2. In the resolution phase of inflammation, the infiltrating leukocytes, which execute the acute innate response, undergo apoptosis and are subsequently cleared by phagocytic macrophages (i.e. efferocytosis). In this course, macrophages undergo reprogramming from inflammatory, to anti-inflammatory, and eventually to resolving macrophages that leave the injury sites. Since engulfment of apoptotic leukocytes is a key signaling step in macrophage reprogramming and resolution of inflammation, we hypothesized that a failed apoptosis in leukocytes in vivo would result in an impaired resolution process. To test this hypothesis, we utilized the Sept4/ARTS^−/− mice, which exhibit resistance to apoptosis in many cell types. During zymosan A-induced peritonitis, Sept4/ARTS^−/− mice exhibited impaired resolution of inflammation, characterized by reduced neutrophil apoptosis, macrophage efferocytosis and expression of pro-resolving mediators. This was associated with increased pro-inflammatory cytokines and reduced anti-inflammatory cytokines, secreted by resolution-phase macrophages. Moreover, ARTS overexpression in leukocytes in vitro promoted an anti-inflammatory behavior. Overall, our results suggest that ARTS is a key master-regulator necessary for neutrophil apoptosis, macrophage efferocytosis and reprogramming to the pro-resolving phenotype during the resolution of inflammation.

ARTS（Sept4_i2）是促凋亡蛋白，是Sept4基因的产物。ARTS作用于线粒体的上游以启动caspase激活。ARTS通过特异性结合XIAP并允许抑制线粒体外膜通透性（MOMP）所需的活性胱天蛋白酶来诱导凋亡。此外，ARTS通过诱导泛素介导的主要抗凋亡蛋白XIAP和Bcl-2降解来促进细胞凋亡。在炎症的分辨率阶段，白细胞浸润，其中执行所述急性先天性应答，经历细胞凋亡和通过巨噬细胞吞噬随后清除（即。胞吐作用）。在此过程中，巨噬细胞经历了从炎症到抗炎的重编程，并最终变成了离开损伤部位的巨噬细胞。由于凋亡性白细胞的吞噬是巨噬细胞重编程和炎症消退的关键信号步骤，因此我们假设体内白细胞凋亡失败会导致消融过程受损。为了验证这一假设，我们利用了Sept4 / ARTS ^-/-小鼠，其在许多细胞类型中均表现出对凋亡的抗性。在酵母聚糖A诱发的腹膜炎期间，Sept4 / ARTS ^-/-小鼠表现出炎症消退受损，其特征在于中性粒细胞凋亡减少，巨噬细胞放血和促分解介质表达。这与分辨期巨噬细胞分泌的促炎细胞因子增加和抗炎细胞因子减少有关。而且，ARTS在体外白细胞中的过表达促进了抗炎行为。总体而言，我们的结果表明，ARTS是嗜中性粒细胞凋亡，巨噬细胞放血和炎症消退过程中重编程为亲表型所必需的关键调控因子。