Mast Cell Tryptase Induces Microglia Activation via Protease-activated Receptor 2 Signaling

Zhang, Shu; Zeng, Xianlu; Yang, Haiwei; Hu, Gang; He, Shaoheng

doi:10.1159/000171029

Cited by 83 publications

(90 citation statements)

References 47 publications

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“…Microglia-derived IL-1β, CXCL8, CCL2, and CCL5 in response to NT can augment the activation of perivascular mast cells, further disrupting the BBB (82-84), perhaps initiating a feedback mechanism. Microglia are stimulated by mast cellderived histamine (85) and tryptase (86). Hence, communication 6 cells) were stimulated with NT (10 nM) for 0-60 min.…”

Section: Discussionmentioning

confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

104

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We had reported elevated serum levels of the peptide neurotensin (NT) in children with autism spectrum disorders (ASD). Here, we show that NT stimulates primary human microglia, the resident immune cells of the brain, and the immortalized cell line of human microglia-SV40. NT (10 nM) increases the gene expression and release (P < 0.001) of the proinflammatory cytokine IL-1β and chemokine (C-X-C motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine and chemokine gene expression and release from human microglia. Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be translocated from the cytoplasm to the cell surface, and to be secreted extracellularly. Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown by phosphorylation of its substrates and inhibition of these responses by drugs that prevent mTOR activation. NT-stimulated responses are inhibited by the flavonoid methoxyluteolin (0.1–1 μM). The data provide a link between sortilin and the pathological findings of microglia and inflammation of the brain in ASD. Thus, inhibition of this pathway using methoxyluteolin could provide an effective treatment of ASD.

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Section: Discussionmentioning

confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

104

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“…In vitro, mast cell tryptase can activate microglia via PAR2 and PAR2 expression on mast cells can be increased by tumour necrosis factor (Zhang et al, 2010;Zhang et al, 2012). There were very low numbers of mast cells in the brain regions examined in this study.…”

Section: Mast Cellsmentioning

confidence: 54%

Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease

et al. 2015

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In neurologically normal brain expression of proteinase-activated receptor-2, activating proteinases and proteinase inhibitors was found in neurons and microglia and did not specifically associate with regions prone to neurodegeneration in Parkinson's disease. InParkinson's disease brain, alterations in the amount of immunoreactivity for proteinaseactivated receptor-2, trypsin-2 and both serpin proteinase inhibitors were found throughout the brain. In neurons, there was a decrease in neurons positive for proteinase inhibitors with increasing Braak α-synuclein stage in the dorsal motor nucleus, locus coeruleus, substantia nigra and primary motor cortex. In contrast, in the cingulate cortex, proteinase-activated receptor-2 expression had a positive correlation to increase with higher Braak α-synuclein stage rating and serpin-A13 was increased in early Parkinson's disease cases compared to controls. In microglia, increased expression occurred for the serpins (dorsal motor nucleus of vagus and substantia nigra), trypsin-2 (dorsal motor nucleus of vagus and primary motor cortex) and proteinase-activated receptor-2 (locus coeruleus and cingulate cortex) that progressively increased with advancing Parkinson's disease severity.In cingulate cortex, the covariate dyskinesia had a significant effect on the the adjusted means for trypsin-2 labelled neurons and microglia and the covariate psychosis had a significant effect on neurons labelled with serpin-A5. While in primary motor cortex, the covariate dyskinesia had a significant effect on the the adjusted means for neurons labelled with serpin-A5, serpin-A13 and trypsin-2. Analysis of Parkinson's disease cases found that serpin and trypsin-2 expression in midbrain and cerebral cortex was different in cases with dyskinesia and psychosis compared to those with no treatment induced side-effects. This study showed that there was altered expression in brain of proteinase-activated receptor-2 and some proteins that can control its function in Parkinson's disease. Given the role of PAR2 expression in Parkinson's disease 3 proteinase-activated receptor-2 in neuroinflammation, drugs that mitigate these changes could be neuroprotective when administered to patients with Parkinson's disease.

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“…MCs produce a vast array of mediators, including proteases and vasoactive amines such as GnRH [13] and histamine [14]. MCs were reported to induce microglial activation and inflammatory mediator release in our previous studies [15,16], suggesting the pivotal role of MCs in the induction of CNS inflammation. These neuromodulators released by MCs result in a variety of inflammatory diseases affected by stress [17].…”

Section: Introductionmentioning

confidence: 95%

“…Yuan reported that mast cell activation induced microglia to release neurotrophin [20]. We previously reported that tryptase and histamine, which are mediators released from MCs, induced microglial activation and inflammatory mediator release [15,16]. However, the effect of MCs on microglial activation is unclear.…”

Section: Introductionmentioning

confidence: 99%

Induction of Microglial Activation by Mediators Released from Mast Cells

Zhang¹,

Wang²,

Dong³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Microglia are the resident immune cells in the brain and play a pivotal role in immune surveillance in the central nervous system (CNS). Brain mast cells are activated in CNS disorders and induce the release of several mediators. Thus, brain mast cells, rather than microglia, are the “first responders” due to injury. However, the functional aspects of mast cell-microglia interactions remain uninvestigated. Methods: Conditioned medium from activated HMC-1 cells induces microglial activation similar to co-culture of microglia with HMC-1 cells. Primary cultured microglia were examined by flow cytometry analysis and confocal microscopy. TNF- alpha and IL-6 were measured with commercial ELISA kits. Cell signalling was analysed by Western blotting. Results: In the present study, we found that the conditioned medium from activated HMC-1 cells stimulated microglial activation and the subsequent production of the pro-inflammatory factors TNF-α and IL-6. Co-culture of microglia and HMC-1 cells with corticotropin-releasing hormone (CRH) for 24, 48 and 72 hours increased TNF-α and IL-6 production. Antagonists of histamine receptor 1 (H₁R), H₄R, proteinase-activated receptor 2 (PAR2) or Toll-like receptor 4 (TLR4) reduced HMC-1-induced pro-inflammatory factor production and MAPK and PI3K/AKT pathway activation. Conclusions: These results imply that activated mast cells trigger microglial activation. Interactions between mast cells and microglia could constitute a new and unique therapeutic target for CNS inflammation-related diseases.

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Mast Cell Tryptase Induces Microglia Activation via Protease-activated Receptor 2 Signaling

Cited by 83 publications

References 47 publications

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease

Induction of Microglial Activation by Mediators Released from Mast Cells

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