title: In vivo molecular markers for pro-inflammatory cytokine M1 stage and resident microglia in trimethyltin-induced hippocampal injury.
abstract: Microglia polarization to the classical M1 activation state is characterized by elevated pro-inflammatory cytokines; however, a full profile has not been generated in the early stages of a sterile inflammatory response recruiting only resident microglia. We characterized the initial M1 state in a hippocampal injury model dependent upon tumor necrosis factor (TNF) receptor signaling for dentate granule cell death. Twenty-one-day-old CD1 male mice were injected with trimethyltin (TMT 2.3 mg/kg, i.p.) and the hippocampus was examined at an early stage (24-h post-dosing) of neuronal death. Glia activation was assessed using a custom quantitative nuclease protection assay. We report elevated mRNA levels for glia response such as ionizing calcium-binding adapter molecule-1 and glial fibrillary acidic protein (Gfap); Fas, hypoxia inducible factor alpha, complement component 1qb, TNF-related genes (Tnf, Tnfaip3, Tnfrsfla); interleukin-1 alpha, Cd44, chemokine (C-C motif) ligand (Ccl)2, Cc14, integrin alpha M, lipocalin (Lcn2), and secreted phosphoprotein 1 (Spp1). These changes occurred in the absence of changes in matrix metalloproteinase 9 and 12, neural cell adhesion molecule, metabotropic glutamate receptor (Grm)3, and Ly6/neurotoxin 1 (Lynx1), as well as, a decrease in neurotrophin 3, glutamate receptor subunit epsilon (Grin)-2b, and neurotrophic tyrosine kinase receptor, type 3. The M2 anti-inflammatory marker, transforming growth factor beta-1 (Tgfb1) was elevated. mRNAs associated with early stage of injury-induced neurogenesis including fibroblast growth factor 21 and Mki67 were elevated. In the "non-injured" temporal cortex receiving projections from the hippocampus, Lynx1, Grm3, and Grin2b were decreased and Gfap increased. Formalin fixed-paraffin-embedded tissue did not generate a comparable profile.
authors.affiliation: Neurotoxicology Group, Division of National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, MD E1-07, Research Triangle Park, NC, 27709, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: McPherson
authors.forename: B A
authors.initials: BA
authors.lastname: Merrick
authors.forename: G J
authors.initials: GJ
authors.lastname: Harry
mesh_terms: D000818:Animals; D015415:Biomarkers; D016923:Cell Death; D016207:Cytokines / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013702:Temporal Lobe / Q000187:drug effects / Q000378:metabolism; D014298:Trimethyltin Compounds / Q000633:toxicity
chemical_list: D015415:Biomarkers; D016207:Cytokines; D012333:RNA, Messenger; D014298:Trimethyltin Compounds; C046488:trimethyltin