Neuroinvasive Listeria monocytogenes Infection Triggers IFN-Activation of Microglia and Upregulates Microglial miR-155

Miao Zhang, Allison. F. Gillaspy, Jenny R. Gipson, Benjamin R. Cassidy, Jessica L. Nave, Misty F. Brewer, Julie A. Stoner, Jie Chen, Douglas A. Drevets
2018 Frontiers in Immunology  
MicroRNA (miR) miR-155 modulates microglial activation and polarization, but its role in activation of microglia during bacterial brain infection is unclear. We studied miR-155 expression in brains of C57BL/6 (B6.WT) mice infected i.p. with the neuro-invasive bacterial pathogen Listeria monocytogenes (L. monocytogenes). Infected mice were treated with ampicillin starting 2 days (d) post-infection (p.i.) and analyzed 3d, 7d, and 14d p.i. Virulent L. monocytogenes strains EGD and 10403s
more » ... nd 10403s upregulated miR-155 in whole brain 7 d p.i. whereas infection with avirulent, non-neurotropic hly or actA L. monocytogenes mutants did not. Similarly, infection with virulent but not mutated bacteria upregulated IFN-γ mRNA in the brain at 7 d p.i. Upregulation of miR-155 in microglia was confirmed by qPCR of flow cytometry-sorted CD45 int CD11b pos brain cells. Subsequently, brain leukocyte influxes and gene expression in sorted microglia were compared in L. monocytogenes-infected B6.WT and B6.Cg-Mir155tm1.1Rsky/J (B6.miR-155 −/− ) mice. Brain influxes of Ly-6C high monocytes and upregulation of IFN-related genes in microglia were similar to B6.WT mice at 3 d p.i. In contrast, by d 7 p.i. expressions of microglial IFN-related genes, including markers of M1 polarization, were significantly lower in B6.miR-155 −/− mice and by 14 d p.i., influxes of activated T-lymphocytes were markedly reduced. Notably, CD45 high CD11b pos brain cells from B6.miR-155 −/− mice isolated at 7 d p.i. expressed 2-fold fewer IFN-γ transcripts than did cells from B6.WT mice suggesting reduced IFN-γ stimulation contributed to dampened gene expression in B6.miR-155 −/− microglia. Lastly, in vitro stimulation of 7 d p.i. brain cells with heat-killed L. monocytogenes induced greater production of TNF in B6.miR-155 −/− microglia than in B6.WT microglia. Thus, miR-155 affects brain inflammation by multiple mechanisms during neuroinvasive L. monocytogenes infection. Peripheral miR-155 promotes brain inflammation through its required role in optimal development of IFN-γ-secreting lymphocytes that enter the brain and activate microglia. Microglial miR-155 promotes M1 polarization, and also inhibits inflammatory responses to stimulation by heat-killed L. monocytogenes, perhaps by targeting Tab2.
doi:10.3389/fimmu.2018.02751 fatcat:ej7ipbbfo5hnrbiaeqmbfbosue