title: Microglial CD14 activated by iNOS contributes to neuroinflammation in cerebral ischemia.
abstract: Stroke is one of the most frequent causes of death and disability worldwide. Cerebral ischemia is the major insult of stroke and induces acute inflammation by triggering excessive production of proinflammatory cytokines, leading to the exacerbation of primary brain damage. Toll-like receptor (TLR)- and nitric oxide-mediated signaling pathways have been identified under ischemic stress. However, the interaction between these two pathways in controlling proinflammatory cytokines has not been well addressed during cerebral ischemia. Adult male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) for stroke induction. The MCAO procedure resulted in a significant infarct in the brain after 24h. The infarcted side of the brain had marked elevation of TNF-α gene and protein expression, compared to the sham brain. The expression of CD14, a co-receptor of TLR4, was induced by MCAO, while the expression of TLR4 remained unchanged. The levels of inducible nitric oxide synthase (iNOS) and nitrotyrosine were also upregulated in the infracted side of the brain. Correspondingly, exposing murine microglial BV2 cells to hypoxia (1% O2) for 20h resulted in an increased expression of TNF-α, CD14, iNOS, and nitrotyrosine. When BV2 cells were treated with l-canavanine, an iNOS selective inhibitor, the elevation of TNF-α and CD14 induced by hypoxia was inhibited. This inhibition was associated with an increase of IκB. These results suggest that the upregulation of TNF-α production in ischemic stroke is partially through increasing iNOS, and then CD14 expression leading to the activation of the NF-κB pathway in microglia.
authors: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors: Mian
authors: M
authors: Zhou
authors: Christie M
authors: CM
authors: Wang
authors: Weng-Lang
authors: WL
authors: Yang
authors: Ping
authors: P
authors: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism*; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse