Signal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammation

Abstract

Activation of microglia is a common denominator and a pathophysiological hallmark of the central nervous system (CNS) disorders. Damage or CNS disorders can trigger inflammatory responses in resident microglia and initiate a systemic immune system response. Although a repertoire of inflammatory responses differs in those diseases, there is a spectrum of transcriptionally activated genes that encode various mediators such as growth factors, inflammatory cytokines, chemokines, matrix metalloproteinases, enzymes producing lipid mediators, toxic molocules, all of which contribute to neuroinflammation. The initiation, progression and termination of inflammation requires global activation of gene expression, postranscriptional regulation, epigenetic modifications, changes in chromatin structure and these processes are tightly regulated by specific signaling pathways. This review focuses on the function of "master regulators" and epigenetic mechanisms in microglia activation during neuroinflammation. We review studies showing impact of epigenetic enzyme inhibitors on microglia activation in vitro and in vivo, and critically discuss potential of such molecules to prevent/moderate pathological events mediated by microglia under brain pathologies. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

Effects of the iron oxide nanoparticle Molday ION Rhodamine B on the viability and regenerative function of neural stem cells: relevance to clinical translation

“…This phenomenon was substantially more pronounced in the 50 μg case, compared to animals receiving 20 μg MIRB-labeled NSCs, and can be attributed to the observed reduced survival of the 50 μg grafts which led to the release of MIRB from dying cells. In addition, given that active microglia can substantially reduce the viability of grafted cells and alter their function through the expression of specific proinflammatory cytokines and other toxic species, 28 the reduced size of the 50 μg grafts in our study could in part be attributed to such a secondary effect. This concept is supported by the increased presence of microglia surrounding even the 20 μg MIRB-labeled grafts (where no significant cell death/loss was noted), suggesting that MIRB may also be directly affecting the intrinsic biology of NSCs, in particularly how these cells interacted with host immune cells.…”

Transcriptional control of microglia phenotypes in health and disease

“…STAT TFs are pleiotropically expressed and mediate diverse functions such as proliferation, apoptosis, and differentiation in response to cytokines (63). STAT proteins form both homo-and heterodimers and become activated when phosphorylated STAT dimers translocate to the nucleus and bind to genomic elements.…”

The Etiological Role of Microglia in Autism Spectrum Disorder: A Possible Route for Early Intervention

“…Additionally, during the postnatal period, resting state microglia in contact with neuronal synapses are responsible for the pruning of extraneous dendrites (Paolicelli et al, 2011). Moreover, microglia and their associated functions are susceptible to epigenetic alteration induced by gestational insults (Kaminska et al, 2016;Nardone and Elliott, 2016;Squarzoni et al, 2015). We suggest that the pathogenesis of ASD begins with an early gestational insult that disrupts the functioning of fetal microglia via an epigenetic mechanism.…”

“…Specifically miRNA-145, miRNA-214 and miRNA-124 are associated with a shift to an M2-like state and could be targeted for down regulation via the introduction of specifically tailored small inhibitory RNA's (Kaminska et al, 2016). As an example, inhibition of a micro RNA associated with the M1 state, miR-204, was able to reverse conditions induced by activation to an M1-like state (Li et al, 2015).…”