title: Neurons and astroglia govern microglial endotoxin tolerance through macrophage colony-stimulating factor receptor-mediated ERK1/2 signals.
abstract: Endotoxin tolerance (ET) is a reduced responsiveness of innate immune cells like macrophages/monocytes to an endotoxin challenge following a previous encounter with the endotoxin. Although ET in peripheral systems has been well studied, little is known about ET in the brain. The present study showed that brain immune cells, microglia, being different from peripheral macrophages, displayed non-cell autonomous mechanisms in ET formation. Specifically, neurons and astroglia were indispensable for microglial ET. Macrophage colony-stimulating factor (M-CSF) secreted from these non-immune cells was essential for governing microglial ET. Neutralization of M-CSF deprived the neuron-glia conditioned medium of its ability to enable microglia to form ET when microglia encountered two lipopolysaccharide (LPS) treatments. Recombinant M-CSF protein rendered enriched microglia refractory to the second LPS challenge leading to microglial ET. Activation of microglial M-CSF receptor (M-CSFR; also known as CSF1R) and the downstream ERK1/2 signals was responsible for M-CSF-mediated microglial ET. Endotoxin-tolerant microglia in neuron-glia cultures displayed M2-like polarized phenotypes, as shown by upregulation of M2 marker Arg-1, elevated production of anti-inflammatory cytokine interleukin 10, and decreased secretion of pro-inflammatory mediators (tumor necrosis factor α, nitric oxide, prostaglandin E2 and interleukin 1β). Endotoxin-tolerant microglia protected neurons against LPS-elicited inflammatory insults, as shown by reduced neuronal damages in LPS pre-treatment group compared with the group without LPS pre-treatment. Moreover, while neurons and astroglia became injured during chronic neuroinflammation, microglia failed to form ET. Thus, this study identified a distinct non-cell autonomous mechanism of microglial ET. Interactions of M-CSF secreted by neurons and astroglia with microglial M-CSFR programed microglial ET. Loss of microglial ET could be an important pathogenetic mechanism of inflammation-associated neuronal damages.
authors.affiliation: Laboratory of Neurobiology, Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; Institute of Molecular Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Chun-Hsien
authors.initials: CH
authors.lastname: Chu
authors.affiliation: Laboratory of Neurobiology, Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Li
authors.affiliation: Laboratory of Neurobiology, Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Shih-Heng
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Laboratory of Neurobiology, Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; Graduate Institute of Medical Sciences, National Defense Medical Center, Department of Pediatrics, Tri-Service General Hospital, Taipei 11401, Taiwan.
authors.forename: Chih-Fen
authors.initials: CF
authors.lastname: Hu
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Yi-Lun
authors.initials: YL
authors.lastname: Chung
authors.affiliation: Department of Neurology, School of Medicine, Kaohsiung Medical University, Kaohsiung 80780, Taiwan.
authors.forename: Shiou-Lan
authors.initials: SL
authors.lastname: Chen
authors.affiliation: Laboratory of Neurobiology, Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Institute of Behavioral Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Institute of Allied Health Sciences, National Cheng Kung University, Tainan 70101, Taiwan; Addiction Research Center, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Ru-Band
authors.initials: RB
authors.lastname: Lu
authors.affiliation: Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China; MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China; Nanjing Biomedical Research Institute, Nanjing University, Nanjing, Jiangsu 210061, China. Electronic address: gaohm@nju.edu.cn.
authors.forename: Hui-Ming
authors.initials: HM
authors.lastname: Gao
authors.affiliation: Laboratory of Neurobiology, Division of Intramural Research, National Institutes of Health/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; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D004731:Endotoxins; D007249:Inflammation / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D000066829:Neuroprotection / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*
chemical_list: D004731:Endotoxins; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: Astroglia; CSF1R; ERK1/2; Endotoxin tolerance; M-CSF; M2-like microglia; Microglia; Neurons; Neuroprotection