Macrophage Matrix Metalloproteinase-12 Dampens Inflammation and Neutrophil Influx in Arthritis

• Published in: Cell reports (Cambridge) Vol. 9; no. 2; pp. 618 - 632
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.10.2014; Elsevier
• Subjects: Actins - metabolism; Animals; Arthritis, Experimental - immunology; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Cartilage - pathology; Cell Line; Complement Activation; Complement C3 - immunology; Extracellular Traps - metabolism; Fibrin - metabolism; Macrophages - metabolism; Male; Matrix Metalloproteinase 12 - genetics; Matrix Metalloproteinase 12 - metabolism; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils - immunology; Neutrophils - metabolism; Peritonitis - immunology; Peritonitis - metabolism; Prothrombin - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.09.006

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. [Display omitted] •Macrophages resolve inflammation via matrix metalloproteinase 12 (MMP12)•MMP12 dampens neutrophil infiltration and clears actin and fibrin from NETs•MMP12 terminates complement activation and increases phagocytosis•By activation of prothrombin in vivo, MMP12 exhibits procoagulant activity Using TAILS proteomics, Bellac et al. now demonstrate that macrophage MMP12 executes multiple protective roles in vivo in inflammation resolution. In arthritis, MMP12 counters neutrophil influx, terminates complement activation, accelerates coagulation, and clears NETs of actin and fibrin to dampen and prepare for the resolution of inflammation.