Bellac Caroline L, Dufour Antoine, Krisinger Michael J, Loonchanta Anantasak, Starr Amanda E, Auf dem Keller Ulrich, Lange Philipp F, Goebeler Verena, Kappelhoff Reinhild, Butler Georgina S, Burtnick Leslie D, Conway Edward M, Roberts Clive R, Overall Christopher M
Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Cell Rep. 2014 Oct 23;9(2):618-32. doi: 10.1016/j.celrep.2014.09.006. Epub 2014 Oct 9.
Resolution of inflammation reduces pathological tissue destruction and restores tissue homeostasis. Here, we used a proteomic protease substrate discovery approach, terminal amine isotopic labeling of substrates (TAILS), to analyze the role of the macrophage-specific matrix metalloproteinase-12 (MMP12) in inflammation. In murine peritonitis, MMP12 inactivates antithrombin and activates prothrombin, prolonging the activated partial thromboplastin time. Furthermore, MMP12 inactivates complement C3 to reduce complement activation and inactivates the chemoattractant anaphylatoxins C3a and C5a, whereas iC3b and C3b opsonin cleavage increases phagocytosis. Loss of these anti-inflammatory activities in collagen-induced arthritis in Mmp12(-/-) mice leads to unresolved synovitis and extensive articular inflammation. Deep articular cartilage loss is associated with massive neutrophil infiltration and abnormal DNA neutrophil extracellular traps (NETs). The NETs are rich in fibrin and extracellular actin, which TAILS identified as MMP12 substrates. Thus, macrophage MMP12 in arthritis has multiple protective roles in countering neutrophil infiltration, clearing NETs, and dampening inflammatory pathways to prepare for the resolution of inflammation.
炎症的消退可减少病理性组织破坏并恢复组织稳态。在此，我们采用蛋白质组学蛋白酶底物发现方法，即底物末端胺同位素标记法（TAILS），来分析巨噬细胞特异性基质金属蛋白酶-12（MMP12）在炎症中的作用。在小鼠腹膜炎中，MMP12使抗凝血酶失活并激活凝血酶原，延长活化部分凝血活酶时间。此外，MMP12使补体C3失活以减少补体激活，并使趋化因子过敏毒素C3a和C5a失活，而iC3b和C3b调理素的裂解则增加吞噬作用。在Mmp12(-/-)小鼠的胶原诱导性关节炎中，这些抗炎活性的丧失导致滑膜炎无法消退和广泛的关节炎症。深层关节软骨丧失与大量中性粒细胞浸润和异常的中性粒细胞胞外陷阱（NETs）DNA有关。NETs富含纤维蛋白和细胞外肌动蛋白，TAILS将其鉴定为MMP12底物。因此，关节炎中的巨噬细胞MMP12在对抗中性粒细胞浸润、清除NETs以及抑制炎症途径以促进炎症消退方面具有多种保护作用。
