Aswad Miran, Assi Simaan, Schif-Zuck Sagie, Ariel Amiram
Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa 3498838, Israel; and.
Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Haifa 3498838, Israel.
J Immunol. 2017 Aug 15;199(4):1393-1404. doi: 10.4049/jimmunol.1502542. Epub 2017 Jul 3.
The engulfment of apoptotic polymorphonuclear cells (PMN) during the resolution of inflammation leads to macrophage reprogramming culminating in reduced proinflammatory and increased anti-inflammatory mediator secretion. The atypical chemokine receptor D6/ACKR2 is expressed on apoptotic PMN and plays an important role in regulating macrophage properties during and after engulfment. In this study, we found that the inflammatory chemokine CCL5 is mostly retained (75%) during the resolution of zymosan A peritonitis in mice. Moreover, this chemokine is secreted by resolution-phase macrophages (2.5 ng/ml) and promotes their reprogramming in vivo in D6 mice (2-fold increase in IL-10/IL-12 ratio) but not their D6 counterparts. In addition, CCL5 enhanced macrophage reprogramming ex vivo exclusively when bound to D6 apoptotic PMN. Signaling through p38MAPK and JNK in reprogrammed macrophages was enhanced by CCL5-bound apoptotic PMN (3.6-4 fold) in a D6-dependent manner, and was essential for reprogramming. Thus, CCL5 exerts a novel proresolving role on macrophages when acting in concert with apoptotic PMN-expressed D6.
在炎症消退过程中，凋亡的多形核细胞（PMN）被吞噬导致巨噬细胞重编程，最终减少促炎介质分泌并增加抗炎介质分泌。非典型趋化因子受体D6/ACKR2在凋亡的PMN上表达，并在吞噬过程中和吞噬后调节巨噬细胞特性方面发挥重要作用。在本研究中，我们发现炎性趋化因子CCL5在小鼠酵母聚糖A腹膜炎消退过程中大部分被保留（75%）。此外，这种趋化因子由消退期巨噬细胞分泌（2.5 ng/ml），并在D6小鼠体内促进其重编程（IL-10/IL-12比值增加2倍），但对其D6缺失的对应物则无此作用。此外，只有当CCL5与D6凋亡PMN结合时，它才能在体外增强巨噬细胞重编程。CCL5结合的凋亡PMN以D6依赖的方式增强了重编程巨噬细胞中通过p38MAPK和JNK的信号传导（3.6 - 4倍），并且这对重编程至关重要。因此，当与凋亡PMN表达的D6协同作用时，CCL5对巨噬细胞发挥一种新的促消退作用。
