Paradoxical attenuation of neuroinflammatory response upon LPS challenge in miR-146b deficient mice

Abstract

The miR-146 family consists of two microRNAs (miRNAs), miR-146a and miR-146b (miR-146a/b), both of which are known to suppress immune responses in a variety of conditions. Here, we studied how constitutive deficiency of miR-146b (Mir146b-/-) affects lipopolysaccharide (LPS)-induced neuroinflammation in mice. Our experiments demonstrated that miR-146b deficiency results in the attenuation of LPS-induced neuroinflammation, as it was evidenced by the reduction of sickness behavior, a decrease in the inflammatory status of microglia, and the loss of morphological signs of microglial activation in the hippocampus. Gene expression analysis revealed that LPS-induced upregulation of hippocampal pro-inflammatory cytokines is attenuated in Mir146b-/- mice, compared to wild-type (WT) mice. In addition, reduced expression of the NF-κB nuclear protein p65, reduced miR-146 family target TLR4 expression and relatively stronger upregulation of miR-146a was found in Mir146b-/- mice as compared to WT mice upon LPS challenge. Compensatory upregulation of miR-146a can explain the attenuation of the LPS-induced neuroinflammation. This was supported by experiments conducted with miR-146a/b deficient mice (Mir146a/b-/-), which demonstrated that additional deletion of the miR-146a led to the restoration of LPS-induced sickness behavior and proinflammatory cytokines. Our experiments also showed that the observed upregulation of miR-146a in Mir146b-/- mice is due to the overexpression of a miR-146a transcription inducer, interferon regulatory factor 7 (Irf7). Altogether, our results show the existence of crosstalk between miR-146a and mir-146b in the regulation of LPS-induced neuroinflammation.

Use of microRNAs as Diagnostic, Prognostic, and Therapeutic Tools for Glioblastoma

“…Both miRNAs arise from the same precursor and are negative regulators of the immune response. These miRNAs are highly expressed in microglia and other immune cells [ 132 , 133 ]. Although tightly linked, both miRNAs are usually studied individually and have distinct targets, although there is evidence that one can rescue the function of the other [ 132 ].…”

“…These miRNAs are highly expressed in microglia and other immune cells [ 132 , 133 ]. Although tightly linked, both miRNAs are usually studied individually and have distinct targets, although there is evidence that one can rescue the function of the other [ 132 ]. Both miR-146a-5p and miR-146b-5p are downregulated in GB and have targets involved in cell proliferation, migration, invasion, stemness, and chemo-resistance [ 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 ].…”