Abstract
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 Δhly or ΔactA 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 CD45intCD11bpos 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-6Chigh 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, CD45highCD11bpos 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.
Highlights
Severe bacterial infections such as meningitis and sepsis trigger CNS inflammatory pathways that are key drivers of neurologic damage and dysfunction [1,2,3]
Manipulating microglial miR expression in animal models of inflammatory diseases of the CNS can have salutary effects suggesting a potential for exerting similar benefits when CNS inflammation is triggered by bacterial infection [13]
The goal of these studies was to analyze miR-155 expression and function during neuroinvasive bacterial infection and its treatment with antibiotics. For this we modified the mouse model of experimental listeriosis such that B6.WT mice received a lethal inoculum of L. monocytogenes EGD i.p, were treated with antibiotics to kill L. monocytogenes starting 48 h post-infection (p.i.) (Figure 1A)
Summary
Severe bacterial infections such as meningitis and sepsis trigger CNS inflammatory pathways that are key drivers of neurologic damage and dysfunction [1,2,3]. Corticosteroids are the principal means used in clinical practice to ameliorate brain inflammation during bacterial meningitis [1]. This treatment clearly benefits some patients, but recent analyses show it does not reduce mortality and severe neurological sequelae in all groups of patients [4,5,6]. Activated microglia and the pro-inflammatory mediators they produce can affect cognitive function or cause mood disorders, and are key contributors to poor outcomes in bacterial meningitis and sepsis [8,9,10]. Manipulating microglial miR expression in animal models of inflammatory diseases of the CNS can have salutary effects suggesting a potential for exerting similar benefits when CNS inflammation is triggered by bacterial infection [13]
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