Experimental arthritis is dependent on mouse mast cell protease-5

Richard L. Stevens*, H. Patrick McNeil, Lislaine A. Wensing, Kichul Shin, G. William Wong, Philip M. Hansbro, Steven A. Krilis

*Corresponding author for this work

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3 Citations (Scopus)

Abstract

The constitutive heparin+ (HP) mast cells (MCs) in mice express mouse MC protease (mMCP)-5 and carboxypeptidase A (mMC-CPA). The amino acid sequence of mMCP-5is most similar to that of human chymase-1, as are the nucleotide sequences of their genes and transcripts. Using a homologous recombination approach, a C57BL/6 mouse line was created that possessed a disrupted mMCP-5 gene. The resulting mice were fertile and had no obvious developmental abnormality. Lack of mMCP-5 protein did not alter the granulation of the IL-3/IL-9-dependent mMCP-2+ MCs in the jejunal mucosa of Trichinella spiralis-infected mice. In contrast, the constitutive HP+ MCs in the tongues of mMCP-5-null mice were poorly granulated and lacked mMC-CPA protein. Bone marrow-derived MCs were readily developed from the transgenic mice using IL-3. Although these MCs contained high levels of mMC-CPA mRNA, they also lacked the latter exopeptidase. mMCP-5 protein is therefore needed to target translated mMC-CPA to the secretory granule along with HP-containing serglycin proteoglycans. Alternately, mMCP-5 is needed to protect mMC-CPA from autolysis in the cell's granules. Fibronectin was identified as a target of mMCP-5, and the exocytosis of mMCP-5 from the MCs in the mouse's peritoneal cavity resulted in the expression of metalloproteinase protease-9, which has been implicated in arthritis. In support of the latter finding, experimental arthritis was markedly reduced in mMCP-5-null mice relative to wild-type mice in two disease models.

Original languageEnglish
Pages (from-to)5392-5404
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number13
Early online date13 Feb 2017
DOIs
Publication statusPublished - 31 Mar 2017

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    Stevens, R. L., McNeil, H. P., Wensing, L. A., Shin, K., Wong, G. W., Hansbro, P. M., & Krilis, S. A. (2017). Experimental arthritis is dependent on mouse mast cell protease-5. Journal of Biological Chemistry, 292(13), 5392-5404. https://doi.org/10.1074/jbc.M116.773416