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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 upregulated miR-155 in whole brain 7 d p.i. whereas infection with avirulent, non-neurotropic Δ hly  or Δ 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 .

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