title: Mast cells contribute to autoimmune inflammatory arthritis via their tryptase/heparin complexes.
abstract: Although mast cells (MCs) often are abundant in the synovial tissues of patients with rheumatoid arthritis, the contribution of MCs to joint inflammation and cartilage loss remains poorly understood. MC-restricted tryptase/heparin complexes have proinflammatory activity, and significant amounts of human tryptase beta (hTryptase-beta) are present in rheumatoid arthritis synovial fluid. Mouse MC protease-6 (mMCP-6) is the ortholog of hTryptase-beta, and this serine protease is abundant in the synovium of arthritic mice. We now report that C57BL/6 (B6) mice lacking their tryptase/heparin complexes have attenuated arthritic responses, with mMCP-6 as the dominant tryptase responsible for augmenting neutrophil infiltration in the K/BxN mouse serum-transfer arthritis model. While inflammation in this experimental arthritis model was not dependent on protease-activated receptor-2, it was dependent on the chemokine receptor CXCR2. In support of the latter data, exposure of synovial fibroblasts to hTryptase-beta/heparin or mMCP-6/heparin complexes resulted in expression of the neutrophil chemotactic factors CXCL1/KC, CXCL5/LIX, and CXCL8/IL-8. Our proteomics, histochemistry, and immunohistochemistry data also revealed substantial loss of cartilage-derived aggrecan proteoglycans in the arthritic joints of wild-type B6 mice but not mMCP-6-null B6 mice. These observations demonstrate the functional contribution of MC-restricted tryptase/heparin complexes in the K/BxN mouse arthritis model and connect our mouse findings with rheumatoid arthritis pathophysiology.
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kichul
authors.initials: K
authors.lastname: Shin
authors.forename: Peter A
authors.initials: PA
authors.lastname: Nigrovic
authors.forename: James
authors.initials: J
authors.lastname: Crish
authors.forename: Eric
authors.initials: E
authors.lastname: Boilard
authors.forename: H Patrick
authors.initials: HP
authors.lastname: McNeil
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Larabee
authors.forename: Roberto
authors.initials: R
authors.lastname: Adachi
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gurish
authors.forename: Reuben
authors.initials: R
authors.lastname: Gobezie
authors.forename: Richard L
authors.initials: RL
authors.lastname: Stevens
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
mesh_terms: D000581:Amidohydrolases / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D001327:Autoimmune Diseases / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D006493:Heparin / Q000031:analogs & derivatives* / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011509:Proteoglycans / Q000502:physiology*; D015238:Sulfotransferases / Q000502:physiology; D053802:Tryptases / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; D011509:Proteoglycans; C509190:Tpsb2 protein, mouse; C036090:heparin proteoglycan; D006493:Heparin; C491855:Ndst2 protein, mouse; D015238:Sulfotransferases; C509222:Tpsab1 protein, mouse; D053802:Tryptases; D000581:Amidohydrolases