title: Substance P enhances microglial density in the substantia nigra through neurokinin-1 receptor/NADPH oxidase-mediated chemotaxis in mice.
abstract: 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.
authors.affiliation: 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 wangq4@niehs.nih.gov.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Oyarzabal
authors.affiliation: Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Wilson
authors.affiliation: Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.affiliation: Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002633:Chemotaxis; D004789:Enzyme Activation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000502:physiology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013373:Substance P / Q000502:physiology*; D013378:Substantia Nigra / Q000166:cytology* / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D018040:Receptors, Neurokinin-1; D013481:Superoxides; D013373:Substance P; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta
keywords: Parkinson's disease; chemotaxis; microglia distribution