Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis

Caroline L. Bellac, Antoine Dufour, Michael J. Krisinger, Anantasak Loonchanta, Amanda E. Starr, Ulrich auf dem Keller, Philipp F. Lange, Verena Goebeler, Reinhild Kappelhoff, Georgina S. Butler, Leslie D. Burtnick, Edward M. Conway, Clive R. Roberts, Christopher M. Overall*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
JournalCell Reports
Volume9
Issue number2
Pages (from-to)618-632
ISSN2211-1247
DOIs
Publication statusPublished - 2014
Externally publishedYes

Cite this

Bellac, C. L., Dufour, A., Krisinger, M. J., Loonchanta, A., Starr, A. E., auf dem Keller, U., Lange, P. F., Goebeler, V., Kappelhoff, R., Butler, G. S., Burtnick, L. D., Conway, E. M., Roberts, C. R., & Overall, C. M. (2014). Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis. Cell Reports, 9(2), 618-632. https://doi.org/10.1016/j.celrep.2014.09.006