The distribution of microglia varies greatly throughout the brain. The substantia nigra (SN) contains the highest density of microglia among different brain regions. However, the mechanism underlying this uneven distribution remains unclear. Substance P (SP) is a potent proinflammatory neuropeptide with high concentrations in the SN. We recently demonstrated that SP can regulate nigral microglial activity. In the present study, we further investigated the involvement of SP in modulating nigral microglial density in postnatal developing mice. Nigral microglial density was quantified in wild-type (WT) and SP-deficient mice from postnatal day 1 (P1) to P30. SP was detected at high levels in the SN as early as P1 and microglial density did not peak until around P30 in WT mice. SP-deficient mice (TAC1−/−) had a significant reduction in nigral microglial density. No differences in the ability of microglia to proliferate were observed between TAC1−/− and WT mice, suggesting that SP may alter microglial density through chemotaxic recruitment. SP was confirmed to dose-dependently attract microglia using a trans-well culture system. Mechanistic studies revealed that both the SP receptor neurokinin-1 receptor (NK1R) and the superoxide-producing enzyme NADPH oxidase (NOX2) were necessary for SP-mediated chemotaxis in microglia. Furthermore, genetic ablation and pharmacological inhibition of NK1R or NOX2 attenuated SP-induced microglial migration. Finally, protein kinase Cδ (PKCδ) was recognized to couple SP/NK1R-mediated NOX2 activation. Altogether, we found that SP partly accounts for the increased density of microglia in the SN through chemotaxic recruitment via a novel NK1R–NOX2 axis-mediated pathway.
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Research Article|
July 29 2015
Substance P enhances microglial density in the substantia nigra through neurokinin-1 receptor/NADPH oxidase-mediated chemotaxis in mice
Qingshan Wang;
*Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
†Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 Western Section, Lvshun South Street, Dalian, Liaoning, 116044, PR China
Correspondence: Qingshan Wang (email wangq4@niehs.nih.gov).
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Esteban Oyarzabal;
Esteban Oyarzabal
*Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
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Belinda Wilson;
Belinda Wilson
*Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
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Li Qian;
Li Qian
*Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
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Jau-Shyong Hong
Jau-Shyong Hong
*Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
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Publisher: Portland Press Ltd
Received:
January 05 2015
Revision Received:
May 27 2015
Accepted:
June 22 2015
Accepted Manuscript online:
June 22 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2015 Authors; published by Portland Press Limited
2015
Clin Sci (Lond) (2015) 129 (8): 757–767.
Article history
Received:
January 05 2015
Revision Received:
May 27 2015
Accepted:
June 22 2015
Accepted Manuscript online:
June 22 2015
Citation
Qingshan Wang, Esteban Oyarzabal, Belinda Wilson, Li Qian, Jau-Shyong Hong; Substance P enhances microglial density in the substantia nigra through neurokinin-1 receptor/NADPH oxidase-mediated chemotaxis in mice. Clin Sci (Lond) 1 October 2015; 129 (8): 757–767. doi: https://doi.org/10.1042/CS20150008
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