Proteome analysis of mast cell releasates reveals a role for chymase in the regulation of coagulation factor XIIIA levels via proteolytic degradation - 18/04/17
Abstract |
Background |
Mast cells are significantly involved in IgE-mediated allergic reactions; however, their roles in health and disease are incompletely understood.
Objective |
We aimed to define the proteome contained in mast cell releasates on activation to better understand the factors secreted by mast cells that are relevant to the contribution of mast cells in diseases.
Methods |
Bone marrow–derived cultured mast cells (BMCMCs) and peritoneal cell–derived mast cells were used as “surrogates” for mucosal and connective tissue mast cells, respectively, and their releasate proteomes were analyzed by mass spectrometry.
Results |
Our studies showed that BMCMCs and peritoneal cell–derived mast cells produced substantially different releasates following IgE-mediated activation. Moreover, we observed that the transglutaminase coagulation factor XIIIA (FXIIIA) was one of the most abundant proteins contained in the BMCMC releasates. Mast cell–deficient mice exhibited increased FXIIIA plasma and activity levels as well as reduced bleeding times, indicating that mast cells are more efficient in their ability to downregulate FXIIIA than in contributing to its amounts and functions in homeostatic conditions. We found that human chymase and mouse mast cell protease-4 (the mouse homologue of human chymase) had the ability to reduce FXIIIA levels and function via proteolytic degradation. Moreover, we found that chymase deficiency led to increased FXIIIA amounts and activity, as well as reduced bleeding times in homeostatic conditions and during sepsis.
Conclusions |
Our study indicates that the mast cell protease content can shape its releasate proteome. Moreover, we found that chymase plays an important role in the regulation of FXIIIA via proteolytic degradation.
Le texte complet de cet article est disponible en PDF.Key words : Mast cells, proteases, chymase, proteomics
Abbreviations used : BMCMCs, CLP, CPA, CTMC, FXIIIA, MMC, mMCP, PCMCs
Plan
| Research for this work was supported by grants for A.M.P. from the National Institutes of Health (NIH) (grant no. HL113351-01) and the American Heart Association (grant no. 12GRNT9680021), for R.G.J. from the NIH (grant no. 5R00HL103768-04), and for N.J.S. by a fellowship from the American Association of Immunologists (2015 AAI Careers in Immunology Fellowship). N.J.W. is supported, in part, by the National Center for Advancing Translational Sciences (grant no. KL2 TR000421), a component of the NIH. S.R.R. was supported by the Parker B. Francis Fellowship. M.A. was supported by the Swedish Research Council. This work is supported in part by the University of Washington's Proteomics Resource (grant no. UWPR95794). |
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| Disclosure of potential conflict of interest: N. J. Shubin declares a grant from the American Academy of Immunologists. M. Abrink declares a grant from the Swedish Research Council. N. J. White declares grants/grants pending from the National Institutes of Health (NIH) and the US Department of Defense and is a board member, has provided consultancy to, and holds stock with Stasys Medical Corp. S. R. Reeves declares grants/grants pending from Parker B. Francis Foundation and the National Heart Lung and Blood Institute (NHLBI). R. G. James declares a grant from the NIH, NHLBI. T. Vaisar declares a grant from the NIH. A. M. Piliponsky declares grants from the NIH and the American Heart Association. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 139 - N° 1
P. 323-334 - janvier 2017 Retour au numéro
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