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: Kichul Shin, Peter A Nigrovic, James Crish, Eric Boilard, H Patrick McNeil, Katherine S Larabee, Roberto Adachi, Michael F Gurish, Reuben Gobezie, Richard L Stevens, David M Lee
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 1 Pg. 647-56 (Jan 01 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19109198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Proteoglycans
• Tpsb2 protein, mouse
• heparin proteoglycan
• Heparin
• Ndst2 protein, mouse
• Sulfotransferases
• Tpsab1 protein, mouse
• Tryptases
• Amidohydrolases

Topics

• Amidohydrolases (physiology)
• Amino Acid Sequence
• Animals
• Arthritis, Experimental (enzymology, immunology, pathology)
• Autoimmune Diseases (enzymology, immunology, pathology)
• Heparin (analogs & derivatives, physiology)
• Humans
• Inflammation Mediators (physiology)
• Mast Cells (enzymology, immunology, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Molecular Sequence Data
• Proteoglycans (physiology)
• Sulfotransferases (physiology)
• Tryptases (physiology)