Epigenetic Regulations of Microglia/Macrophage Polarization in Ischemic Stroke

Abstract

Ischemic stroke is one of the leading causes of death and disability worldwide. Microglia/macrophages (MMs)-mediated neuroinflammation contributes significantly to the pathological process of ischemic brain injury. Microglia, serving as resident innate immune cells in the central nervous system, undergo pro-inflammatory phenotype or anti-inflammatory phenotype in response to the microenvironmental changes after cerebral ischemia. Emerging evidence suggests that epigenetics modifications, reversible modifications of the phenotype without changing the DNA sequence, could play a pivotal role in regulation of MM polarization. However, the knowledge of the mechanism of epigenetic regulations of MM polarization after cerebral ischemia is still limited. In this review, we present the recent advances in the mechanisms of epigenetics involved in regulating MM polarization, including histone modification, non-coding RNA, and DNA methylation. In addition, we discuss the potential of epigenetic-mediated MM polarization as diagnostic and therapeutic targets for ischemic stroke. It is valuable to identify the underlying mechanisms between epigenetics and MM polarization, which may provide a promising treatment strategy for neuronal damage after cerebral ischemia.

Epigenetics and Neuroinflammation Associated With Neurodevelopmental Disorders: A Microglial Perspective

“…miRNAs play important roles in the regulation of neurodevelopment by modulating the expression of target genes via binding to the 3′-untranslated regions ( Thomas et al, 2018 ). miRNAs are also involved in microglial function ( Butovsky and Weiner, 2018 ; Cheray and Joseph, 2018 ; Guo et al, 2019 ; Qiu M. et al, 2021 ; Zhao et al, 2021 ). The expression of these miRNAs is epigenetically regulated by prenatal exposure ( Knopik et al, 2019 ; Sushma et al, 2021 ).…”

Regulation of N6-methyladenosine (m6A) RNA methylation in microglia-mediated inflammation and ischemic stroke

“…MMs are the primary immune cells defending against CNS damage and are crucial in regulating brain homeostasis ( Liu et al, 2019b ; Qiu et al, 2021 ). After cerebral ischemia, local microglia and peripheral macrophages are quickly activated and regulate neuropathological processes to carry out functional recovery ( Zhao et al, 2017 ; Li and Barres, 2018 ).…”

“…M1-like MMs have been shown to breach the BBB and aggravate neurological impairments by producing inflammatory cytokines like TNF, IL-1β, and inducible nitric oxide synthase (iNOS). In contrast, M2-like MMs support tissue repair by clearing cell debris, promoting neurogenesis, angiogenesis, axon regeneration, and releasing anti-inflammatory cytokines such as arginase-1 (Arg-1) and IL-10, and neurotrophic factors ( Prinz et al, 2021 ; Qiu et al, 2021 ). Therefore, most of the current studies focus on the ways to inhibit M1 and/or enhance M2 phenotype to control the activation of microglia, to limit inflammatory injury and promote tissue repair to treat IS and improve neuronal survival.…”

“…During stroke occurrence and development, cerebral inflammation plays important roles and was seem as a breakthrough in treatment of stroke (Lyu et al, 2021). Recently, it is showed that epigenetics could regulate the inflammatory response, which suggests novel understanding in inflammation research (Qiu et al, 2021). To better understand the role of m6A modification in the inflammatory response in the brain, we then focus on the 10.3389/fncel.2022.955222 microglia/macrophages that generate an inflammatory response in the brain to gain new insights into neuroprotection following cerebral ischemia.…”

New Insight in HDACs: Potential Therapeutic Targets for the Treatment of Atherosclerosis

“…The levels of several HDAC, HDAC3, and HDAC9 could be stimulated in response to monocyte differentiation to macrophages in LDLR −/− mice kept on an atherogenic diet ( Figure 4 ) ( Rajendrasozhan et al, 2008 ). In addition, myeloid-specific deletion of HDAC9 and HDAC3 mitigates AS by promoting M2 macrophage polarization and reducing proinflammatory gene expression ( Qiu et al, 2021 ). The mechanism of HDAC9 in promoting pro-inflammatory responses and augmenting the effects of atherosclerotic plaque vulnerability involves the binding of HDAC9 to IKKα and β, which contributes to their deacetylation and subsequent activation, thereby finally driving vascular inflammation ( Van den Bossche et al, 2014 ).…”