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

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.