The mouse mast cell–restricted tetramer‐forming tryptases mouse mast cell protease 6 and mouse mast cell protease 7 are critical mediators in inflammatory arthritis

Abstract

Objective. Increased numbers of mast cells (MCs) that express ␤ tryptases bound to heparin have been detected in the synovium of patients with rheumatoid arthritis (RA). The corresponding tryptases in mice are mouse MC protease 6 (mMCP-6) and mMCP-7. Although MCs have been implicated in RA and some animal models of arthritis, no direct evidence for a MC-restricted tryptase in the pathogenesis of inflammatory arthritis has been shown. We created transgenic mice that lack heparin and different combinations of mMCP-6 and mMCP-7, to evaluate the roles of MCrestricted tryptase-heparin complexes in an experimental model of arthritis.Methods. The methylated bovine serum albumin/ interleukin-1␤ (mBSA/IL-1␤) experimental protocol was used to induce inflammatory monarthritis in different mouse strains. Mice were killed at the time of peak disease on day 7, and histochemical methods were used to assess joint pathology.Results. Arthritis was induced in the knee joints of mBSA/IL-1␤-treated mMCP-6 ؉ /mMCP-7 ؊ and mMCP-6 ؊ /mMCP-7 ؉ C57BL/6 mice, and numerous activated MCs that had exocytosed the contents of their secretory granules were observed in the diseased mice. In contrast, arthritis was markedly reduced in heparindeficient mice and in mMCP-6 ؊ /mMCP-7 ؊ C57BL/6 mice.Conclusion. MC-derived tryptase-heparin complexes play important roles in mBSA/IL-1␤-induced arthritis. Because mMCP-6 and mMCP-7 can compensate for each other in this disease model, the elimination of both tryptases is necessary to reveal the prominent roles of these serine proteases in joint inflammation and destruction. Our data suggest that the inhibition of MC-restricted tryptases could have therapeutic potential in the treatment of RA.Rheumatoid arthritis (RA) is an inflammatory disorder of synovial joints characterized by damage to articular structures due to chronic inflammation of the synovium. Numerous cellular participants of innate and adaptive immunity contribute to the pronounced inflammatory processes seen in rheumatoid synovitis. Our group (1-4) and many other investigators (5-14) have obtained data implicating a prominent involvement of mast cells (MCs) and their mediators in RA and some animal models of this autoimmune disorder. On a weight basis, tetramer-forming ␤ tryptases (15)(16)(17)(18)(19) are the most abundant proteins present in the secretory granules of human MCs. Three ␤ tryptase complementary DNAs (designated hTryptase ␤1, ␤2, and ␤3) have been cloned.

Essential role for mast cell tryptase in acute experimental colitis

“…2-5), allowed us to conclude that the most important tryptase in our experimental colitis studies is mMCP-6, the putative mouse ortholog of hTryptase-β. Although there are no comparative studies of MC tryptase in intestinal inflammation, our results are in agreement with those noted in our earlier studies of inflammatory arthritis (11,12).…”

“…These data suggest that another chymase family member (e.g., mMCP-4) has a more prominent role than mMCP-5 in the colitis model. Alternately, there is chymase/elastase-like redundancy in DSS-induced colitis in the mouse, analogous to the tryptase redundancy found in methylated BSA-induced arthritis (11). It also is possible that chymase/elastase-like MC mediators do not play significant roles in acute experimental colitis.…”

“…6 and 7 and Dataset S1). Although mMCP-6 and mMCP-7 are closely related and can have redundant proinflammatory activities in some disease states (11), the substrate preferences of the two tryptases are not identical (9,30). The observation that substantial pathology occurs in DSS-treated 6 + /7 − B6 mice, but in not 6 − /7 + and 6 − /7 − mice (Figs.…”

“…For example, we showed that experimental inflammatory arthritis was significantly attenuated in 6 − /7 − B6 mice and 6 − /7 + B6 mice relative to 6 + /7 − B6 mice (11,12). Increased numbers of hTryptase-β + MCs have been detected in intestinal specimens from patients with ulcerative colitis (UC) and Crohn disease (13).…”

Expressão e caracterização das quimases recombinantes específicas de mastócitos de camundongos (mMCP4 e 5)

“…As proteases ativas são estocadas nos grânulos de mastócitos. Fonte: Pejler et al, 2010. As proteases específicas de mastócitos estão relacionadas com artrite, inflamação alérgica das vias aéreas, angiogênese tumoral, formação de aneurisma aórtico abdominal e glomerulonefrite e na defesa contra bactérias e parasitas MCNEIL et al, 2008;WAERN et al, 2009;SCANDIUZZI et al, 2010;SOUZA-JUNIOR et al, 2012). As proteases também possuem um papel modulador nas reações alérgicas, onde a β-triptase liberada durante a ativação dos mastócitos cliva a molécula de IgE limitando a inflamação alérgica (RAUTER et al, 2008).…”