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In Vivo Molecular Markers for Pro-inflammatory Cytokine M1 Stage and Resident Microglia in Trimethyltin-Induced Hippocampal Injury

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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.

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Acknowledgments

The authors thank the NIEHS Microarray Core for their expert assistant with the initial microarray analysis used for selection of qNPA probes, Dr. Grace Kissling for statistical expertise, and Drs. Stephanie L. Smith-Roe and Chad Blystone of NIEHS for reviewing the final manuscript. This study was funded by the Division of Intramural Research and the Division National Toxicology Program, NIEHS/NIH (1Z01ES101623). The qNPA was conducted at HTG under an NTP contract with technical expertise from Dr John Luecke. The statements, opinions, or conclusions contained within this manuscript do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the United States Government.

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The authors declare no conflict of interest associated with this study.

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  1. 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

    C. A. McPherson & G. J. Harry

  2. Biomolecular Screening Branch, Division of National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

    B. A. Merrick

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  1. C. A. McPherson
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McPherson, C.A., Merrick, B.A. & Harry, G.J. In Vivo Molecular Markers for Pro-inflammatory Cytokine M1 Stage and Resident Microglia in Trimethyltin-Induced Hippocampal Injury. Neurotox Res 25, 45–56 (2014). https://doi.org/10.1007/s12640-013-9422-3

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