title: Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis.
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.
authors.affiliation: 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.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Bellac
authors.affiliation: 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.
authors.forename: Antoine
authors.initials: A
authors.lastname: Dufour
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krisinger
authors.affiliation: 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.
authors.forename: Anantasak
authors.initials: A
authors.lastname: Loonchanta
authors.affiliation: Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Starr
authors.affiliation: 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.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Auf dem Keller
authors.affiliation: 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.
authors.forename: Philipp F
authors.initials: PF
authors.lastname: Lange
authors.affiliation: 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.
authors.forename: Verena
authors.initials: V
authors.lastname: Goebeler
authors.affiliation: 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.
authors.forename: Reinhild
authors.initials: R
authors.lastname: Kappelhoff
authors.affiliation: 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.
authors.forename: Georgina S
authors.initials: GS
authors.lastname: Butler
authors.affiliation: Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Leslie D
authors.initials: LD
authors.lastname: Burtnick
authors.affiliation: 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.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.affiliation: 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.
authors.forename: Clive R
authors.initials: CR
authors.lastname: Roberts
authors.affiliation: 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; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: chris.overall@ubc.ca.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Overall
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002356:Cartilage / Q000473:pathology; D002460:Cell Line; D003167:Complement Activation; D003176:Complement C3 / Q000276:immunology; D065206:Extracellular Traps / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism; D011516:Prothrombin / Q000378:metabolism
chemical_list: D000199:Actins; D003176:Complement C3; D011516:Prothrombin; D005337:Fibrin; D053508:Matrix Metalloproteinase 12