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

Caroline L Bellac1, Antoine Dufour1, Michael J Krisinger2

  • 1Centre 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.

Cell Reports
|October 15, 2014
PubMed

Insights

Matrix metalloproteinase-12 (MMP12) resolves inflammation by regulating blood clotting and immune cell activity. In arthritis, MMP12 protects joints by reducing neutrophil infiltration and clearing neutrophil extracellular traps (NETs).

Area of Science:

  • Biochemistry
  • Immunology
  • Proteomics

Background:

  • Inflammation resolution is crucial for tissue homeostasis.
  • Macrophage-derived matrix metalloproteinase-12 (MMP12) is implicated in inflammatory processes.

Purpose of the Study:

  • To investigate the role of MMP12 in inflammation using a proteomic approach.
  • To elucidate MMP12's substrates and functions in inflammatory conditions.

Main Methods:

  • Terminal amine isotopic labeling of substrates (TAILS) proteomics.
  • Murine models of peritonitis and collagen-induced arthritis (CIA).
  • Analysis of coagulation parameters and complement system components.

Main Results:

  • MMP12 modulates coagulation by inactivating antithrombin and activating prothrombin.
  • MMP12 regulates complement activation by inactivating C3, C3a, and C5a, while promoting phagocytosis via iC3b and C3b cleavage.
  • Mmp12(-/-) mice exhibit unresolved synovitis, extensive articular inflammation, cartilage loss, and increased neutrophil infiltration with abnormal NETs in CIA.
  • TAILS identified fibrin and extracellular actin in NETs as MMP12 substrates.

Conclusions:

  • Macrophage MMP12 plays critical protective roles in inflammation resolution.
  • MMP12 counters neutrophil infiltration, clears NETs, and dampens inflammatory pathways.
  • Targeting MMP12 may offer therapeutic strategies for inflammatory diseases like arthritis.

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