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Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation

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Abstract

Brain inflammation has a critical role in the pathophysiology of brain diseases. Microglia, the resident immune cells in the brain, play an important role in brain inflammation, while brain mast cells are the “first responder” in the injury rather than microglia. Functional aspects of mast cell-microglia interactions remain poorly understood. Our results demonstrated that site-directed injection of the “mast cell degranulator” compound 48/80 (C48/80) in the hypothalamus induced mast cell degranulation, microglial activation, and inflammatory factor production, which initiated the acute brain inflammatory response. “Mast cell stabilizer” disodium cromoglycate (cromolyn) inhibited this effect, including decrease of inflammatory cytokines, reduced microglial activation, inhibition of MAPK and AKT pathways, and repression of protein expression of histamine receptor 1 (H1R), histamine receptor 4 (H4R), protease-activated receptor 2 (PAR2), and toll-like receptor 4 (TLR4) in microglia. We also demonstrated that C48/80 had no effect on microglial activation in mast cell-deficient KitW-sh/W-sh mice. These results implicate that activated brain mast cells trigger microglial activation and stabilization of mast cell inhibits microglial activation-induced central nervous system (CNS) inflammation. Interactions between mast cells and microglia could constitute a new and unique therapeutic target for CNS immune inflammation-related diseases.

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Acknowledgments

This project was sponsored by the National Natural Science Foundation of China (nos. 81102422, 81373398, and 81471410), a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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    Authors and Affiliations

    1. Clinical Research Center, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China

      Hongquan Dong, Xiang Zhang, Yiming Wang & Shu Zhang

    2. Department of Anesthesiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China

      Hongquan Dong, Xiang Zhang & Yanning Qian

    3. Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China

      Xiqiao Zhou

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    1. Hongquan Dong
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    Correspondence to Shu Zhang.

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    Hongquan Dong and Xiang Zhang contributed equally to this work.

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    Dong, H., Zhang, X., Wang, Y. et al. Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation. Mol Neurobiol 54, 997–1007 (2017). https://doi.org/10.1007/s12035-016-9720-x

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