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Published on: January 30, 2014
Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation
Hongquan Dong1,2, Xiang Zhang1,2, Yiming Wang1
1Clinical Research Center, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
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.
Insights
Activated brain mast cells trigger neuroinflammation by activating microglia. Stabilizing mast cells can reduce this inflammation, offering a new therapeutic target for central nervous system (CNS) immune diseases.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
Background:
- Brain inflammation is central to neurological disease pathophysiology.
- Microglia are key immune cells, but mast cells act as the initial responders to brain injury.
- The functional interactions between mast cells and microglia are not well understood.
Purpose of the Study:
- To investigate the role of brain mast cells in initiating neuroinflammation.
- To elucidate the mechanisms of mast cell-microglia interactions in the central nervous system (CNS).
- To explore mast cell stabilization as a therapeutic strategy for CNS inflammatory diseases.
Main Methods:
- Induced mast cell degranulation in the hypothalamus using compound 48/80 (C48/80).
- Administered disodium cromoglycate (cromolyn) to stabilize mast cells.
- Assessed microglial activation, inflammatory cytokine production, and signaling pathways (MAPK, AKT).
- Utilized mast cell-deficient KitW-sh/W-sh mice to confirm mast cell dependence.
Main Results:
- Compound 48/80 triggered mast cell degranulation, leading to microglial activation and inflammatory factor release.
- Cromolyn inhibited C48/80-induced inflammation, reducing cytokines and microglial activation.
- Inhibition by cromolyn involved suppressing MAPK and AKT pathways and key receptors (H1R, H4R, PAR2, TLR4) on microglia.
- C48/80 did not activate microglia in mast cell-deficient mice, confirming mast cell involvement.
Conclusions:
- Activated brain mast cells initiate neuroinflammation by triggering microglial activation.
- Stabilizing mast cells effectively inhibits microglial activation and subsequent CNS inflammation.
- Mast cell-microglia interactions represent a novel therapeutic target for CNS immune inflammatory diseases.
