title: Chemical dampening of Ly6C(hi) monocytes in the periphery produces anti-depressant effects in mice.
abstract: The involvement of systemic immunity in depression pathogenesis promises a periphery-targeting paradigm in novel anti-depressant discovery. However, relatively little is known about druggable targets in the periphery for mental and behavioral control. Here we report that targeting Ly6C(hi) monocytes in blood can serve as a strategy for anti-depressant purpose. A natural compound, ginsenoside Rg1 (Rg1), was firstly validated as a periphery-restricted chemical probe. Rg1 selectively suppressed Ly6C(hi) monocytes recruitment to the inflamed mice brain. The proinflammatory potential of Ly6C(hi) monocytes to activate astrocytes was abrogated by Rg1, which led to a blunted feedback release of CCL2 to recruit the peripheral monocytes. In vitro study demonstrated that Rg1 pretreatment on activated THP-1 monocytes retarded their ability to trigger CCL2 secretion from co-cultured U251 MG astrocytes. CCL2-triggered p38/MAPK and PI3K/Akt activation were involved in the action of Rg1. Importantly, in mice models, we found that dampening Ly6C(hi) monocytes at the periphery ameliorated depression-like behavior induced by neuroinflammation or chronic social defeat stress. Together, our work unravels that blood Ly6C(hi) monocytes may serve as the target to enable remote intervention on the depressed brain, and identifies Rg1 as a lead compound for designing drugs targeting peripheral CCL2 signals.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.|Department of Pharmacy, Nanjing University of Chinese Medicine Affiliated Hospital, Nanjing 210029, Jiangsu, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.|Department of Pharmacy, Affiliated Hospital of Hunan Academy of Chinese Medical Sciences, Changsha 410000, Hunan, China.
authors.forename: Sijing
authors.initials: S
authors.lastname: Ma
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.
authors.forename: An
authors.initials: A
authors.lastname: Kang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
authors.forename: Mengqiu
authors.initials: M
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Nanjing University of Chinese Medicine Affiliated Hospital, Nanjing 210029, Jiangsu, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism*; D000950:Antigens, Ly / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D036145:Ginsenosides / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological
chemical_list: D000928:Antidepressive Agents; D000950:Antigens, Ly; D018932:Chemokine CCL2; D036145:Ginsenosides; C494192:Ly-6C antigen, mouse; C035054:ginsenoside Rg1