Evidence for miR‐181 involvement in neuroinflammatory responses of astrocytes

Abstract

Inflammation is a common component of acute injuries of the central nervous system (CNS) and degenerative disorders such as Alzheimer’s disease. Glial cells play important roles in local CNS inflammation, and an understanding of the roles for microRNAs in glial reactivity in injury and disease settings may therefore enable novel therapeutic interventions. Here we show that the miR-181 family is developmentally regulated and present in high amounts in astrocytes compared to neurons. Over-expression of miR-181c in cultured astrocytes results in increased cell death when exposed to lipopolysaccharide (LPS). We show that miR-181 expression is altered in brain cells in vivo in response to LPS, a model of inflammation, in both wild-type mice and transgenic mice lacking both receptors for the inflammatory cytokine TNF-α. Knockdown of miR-181 enhanced LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-8) and HMGB1, while over-expression of miR-181 resulted in a significant increase in the expression of the anti-inflammatory cytokine IL-10. To assess the effects of miR-181 on the astrocyte transcriptome, we performed gene array and pathway analysis on astrocytes with reduced levels of miR-181b/c. To examine the pool of potential miR-181 targets, we employed a biotin pull-down of miR-181c and microarray analysis. We validated both MeCP2 and XIAP mRNAs as targets of miR-181. These findings suggest that miR-181 plays important roles in the response of astrocytes to inflammatory settings. Further understanding of the role of miR-181 in inflammatory events and CNS injury could lead to novel therapies for CNS disorders with an inflammatory component.

Astrogliosis

“…These instructive signals can derive from many different sources (Fig. 1A) (Bhalala et al 2012;Hutchison et al 2013), and miR regulatory enzymes, such as Dicer (Tao et al 2011), can modulate astrogliosis and reactive astrocyte functions, adding yet another level of potential regulation and specification of functions (Table 1). Thus, intrinsic properties of individual astrocytes, such as epigenetic mechanisms or genetic polymorphisms of receptors and second messengers and other regulators, may impact astrogliosis.…”

“…Deletion of YLK-40/BRP-39, an astrocyte produced anti-inflammatory protein, exacerbates autoimmune disease in mice (Bonneh-Barkay et al 2012). miR-181 decreases astrocyte production of inflammatory cytokines (TNF-a, IL-1b) and increases production of anti-inflammatory cytokines (IL-10) (Hutchison et al 2013). Thus, different signaling mechanisms regulate different aspects of pro-or anti-inflammatory functions of reactive astrocytes.…”

Mesenchymal stem cells-derived exosomal microRNAs contribute to wound inflammation

“…Dan et al suggested that miR-181 upregulation is the primary host protective method against endotoxin shock, as it can switch the immune status from hyperinflammation to endotoxin tolerance by quickly decreasing inflammatory cytokine expression without influencing the expression of anti-inflammatory cytokines (Dan et al, 2014). In an experimental neuroinflammatory model, miR-181 was found to be necessary for the reactive phenotype of astrocytes to inflammatory settings by reprogramming the transcriptional profiles of general cell differentiation and stress responses (Hutchison et al, 2013). These results clearly illustrate that miR-181 plays a central role in anabolic metabolism in immune cells and fine-tunes their immunological functions to prevent overwhelming inflammation during tissue regeneration.…”

Cortisol Supplement Combined with Psychotherapy and Citalopram Improves Depression Outcomes in Patients with Hypocortisolism after Traumatic Brain Injury

“…The HPA axis abnormalities are involved in depression [49]. Patients with hypocortisolism tend to present more distress symptoms, maladaptive coping styles, and schizotypal personality traits [50]. TBI patients induce HPA axis dysfunction in the acute phase of severe TBI patients.…”