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: C A McPherson, B A Merrick, G J Harry
• Journal: Neurotoxicity research (Neurotox Res) Vol. 25 Issue 1 Pg. 45-56 (Jan 2014) ISSN: 1476-3524 [Electronic] United States
• PMID: 24002884 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Biomarkers
• Cytokines
• RNA, Messenger
• Trimethyltin Compounds
• trimethyltin

Topics

• Animals
• Biomarkers
• Cell Death
• Cytokines (metabolism)
• Hippocampus (drug effects, metabolism, pathology)
• Inflammation (genetics, metabolism)
• Male
• Mice
• Microglia (drug effects, metabolism)
• RNA, Messenger (metabolism)
• Temporal Lobe (drug effects, metabolism)
• Trimethyltin Compounds (toxicity)