title: Early activation of STAT3 regulates reactive astrogliosis induced by diverse forms of neurotoxicity.
abstract: Astrogliosis, a cellular response characterized by astrocytic hypertrophy and accumulation of GFAP, is a hallmark of all types of central nervous system (CNS) injuries. Potential signaling mechanisms driving the conversion of astrocytes into "reactive" phenotypes differ with respect to the injury models employed and can be complicated by factors such as disruption of the blood-brain barrier (BBB). As denervation tools, neurotoxicants have the advantage of selective targeting of brain regions and cell types, often with sparing of the BBB. Previously, we found that neuroinflammation and activation of the JAK2-STAT3 pathway in astrocytes precedes up regulation of GFAP in the MPTP mouse model of dopaminergic neurotoxicity. Here we show that multiple mechanistically distinct mouse models of neurotoxicity (MPTP, AMP, METH, MDA, MDMA, KA, TMT) engender the same neuroinflammatory and STAT3 activation responses in specific regions of the brain targeted by each neurotoxicant. The STAT3 effects seen for TMT in the mouse could be generalized to the rat, demonstrating cross-species validity for STAT3 activation. Pharmacological antagonists of the neurotoxic effects blocked neuroinflammatory responses, pSTAT3tyr705 and GFAP induction, indicating that damage to neuronal targets instigated astrogliosis. Selective deletion of STAT3 from astrocytes in STAT3 conditional knockout mice markedly attenuated MPTP-induced astrogliosis. Monitoring STAT3 translocation in GFAP-positive cells indicated that effects of MPTP, METH and KA on pSTAT3tyr705 were localized to astrocytes. These findings strongly implicate the STAT3 pathway in astrocytes as a broadly triggered signaling pathway for astrogliosis. We also observed, however, that the acute neuroinflammatory response to the known inflammogen, LPS, can activate STAT3 in CNS tissue without inducing classical signs of astrogliosis. Thus, acute phase neuroinflammatory responses and neurotoxicity-induced astrogliosis both signal through STAT3 but appear to do so through different modules, perhaps localized to different cell types.
authors.affiliation: Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia, United States of America.
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.affiliation: Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia, United States of America.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kelly
authors.affiliation: School of Pharmacy, West Virginia University, Morgantown, West Virginia, United States of America.
authors.forename: Reyna L
authors.initials: RL
authors.lastname: VanGilder
authors.affiliation: David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sofroniew
authors.affiliation: Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia, United States of America.
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001372:Aza Compounds / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein; D005911:Gliosis / Q000235:genetics / Q000378:metabolism*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D053614:Janus Kinase 2 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D001372:Aza Compounds; C558517:CORT 108297; D005904:Glial Fibrillary Acidic Protein; D006576:Heterocyclic Compounds, 4 or More Rings; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; C528900:glial fibrillary astrocytic protein, mouse; D053614:Janus Kinase 2