miR‐146b Protects the Perinatal Brain against Microglia‐Induced Hypomyelination

Abstract

In the premature newborn, perinatal inflammation mediated by microglia contributes significantly to neurodevelopmental injuries including white matter injury (WMI). Brain inflammation alters development through neuroinflammatory processes mediated by activation of homeostatic microglia toward a pro-inflammatory and neurotoxic phenotype. Investigating immune regulators of microglial activation is crucial to find effective strategies to prevent and treat WMI. Methods: Ex vivo microglial cultures and a mouse model of WMI induced by perinatal inflammation (interleukin-1-beta [IL-1β] and postnatal days 1-5) were used to uncover and elucidate the role of microRNA-146b-5p in microglial activation and WMI. Results: A specific reduction in vivo in microglia of Dicer, a protein required for microRNAs maturation, reduces pro-inflammatory activation of microglia and prevents hypomyelination in our model of WMI. Microglial miRNome analysis in the WMI model identified miRNA-146b-5p as a candidate modulator of microglial activation. Ex vivo microglial cell culture treated with the pro-inflammatory stimulus lipopolysaccharide (LPS) led to overexpression of immunomodulatory miRNA-146b-5p but its drastic reduction in the microglial extracellular vesicles (EVs). To increase miRNA-146b-5p expression, we used a 3DNA nanocarrier to deliver synthetic miRNA-146b-5p specifically to microglia. Enhancing microglial miRNA-146b-5p overexpression significantly decreased LPS-induced activation, downregulated IRAK1, and restored miRNA-146b-5p levels in EVs. In our WMI model, 3DNA miRNA-146b-5p treatment significantly prevented microglial activation, hypomyelination, and cognitive defect induced by perinatal inflammation. Interpretations: These findings support that miRNA-146b-5p is a major regulator of microglia phenotype and could be targeted to reduce the incidence and the severity of perinatal brain injuries and their long-term consequences.

A unique cerebellar pattern of microglia activation in a mouse model of encephalopathy of prematurity

“…By contrast, the cerebellum appears to be particularly sensitive to systemic inflammation during the perinatal period. where (Bokobza et al, 2022;Van Steenwinckel et al, 2019;Veerasammy et al, 2020).…”

Enhanced Cognition and Neurogenesis in miR-146b Deficient Mice

“…In addition, previous studies have shown that electro acupuncture-stimulated hippocampal neurogenesis in the rat model of focal cerebral ischemia and reperfusion was associated with an increased miR-146b expression, while inhibition of miR-146b reduced stimulatory effect of acupuncture on the hippocampal neurogenesis [75]. It should be noted that, aside from the novel neuronal functions of miR-146b described in our study, miR-146b is expressed in microglial cells and is involved in the negative regulation of neuroinflammation [25,27]. Previous studies have demonstrated that focal cerebral ischemia and reperfusion can induce inflammation and that acupuncture is able to reduce neuroinflammation [76].…”

“…As previously miR-146b had been shown to regulate immune responses in variety of cells and tissues [15,17,27], and because microglia can control adult neurogenesis through secretion of various soluble factors including cytokines [68,69], we studied in more detail the morphology of microglia cells. We did not observe signs of microglial activation in Mir146b-/mice.…”

“…As numerous previous studies have demonstrated the immunomodulatory role of miR-146b [25,27], we further explored in more detail microglial morphology, microglial polarization and the expression of Il1b, Tnf, Il18 mRNA. No changes were observed in the density of Iba1-positive microglia (p = 0.8618; Student's t-test; Figure 6A,B).…”

“…Another study in rats has shown that miR-146b overexpression with lentivirus vector could inhibit the proliferation of primary hippocampal neural stem cells [26]. A recent study has identified miR-146b as a candidate modulator of microglial activation [27]. In addition, miR-146b has also been reported to be a prognostic biomarker of gliomas, as it inhibits glioma cell proliferation and migration and induces apoptosis [28][29][30][31].…”