Dynamic Modulation of Microglia/Macrophage Polarization by miR-124 after Focal Cerebral Ischemia

Abstract

Mononuclear phagocytes respond to ischemic stroke dynamically, undergoing an early anti-inflammatory and protective phenotype followed by the pro-inflammatory and detrimental type. These dual roles of microglia/macrophages suggest the need of subtle adjustment of their polarization state instead of broad suppression. The most abundant brain-specific miRNA, miR-124, promotes neuronal differentiation but can also modulate microglia activation and keeps them in a quiescent state. We addressed whether the intracerebral injection of miR-124 in a mouse model of ischemic stroke before or after the peak phase of the pro-inflammatory polarization modifies the pro−/anti- inflammatory balance. In the sub-acute phase, 48 h after stroke, liposomated miR-124 shifted the predominantly pro-inflammatory polarized microglia/macrophages toward the anti-inflammatory phenotype. The altered immune response improved neurological deficit at day 6 after stroke. When miR-124 was injected 10 days after stroke, the pro−/anti- inflammatory ratio was still significantly reduced although to a lower degree and had no effect on recovery at day 14. This study indicates that miR-124 administration before the peak of the pro-inflammatory process of stroke is most effective in support of increasing the rehabilitation opportunity in the sub-acute phases of stroke. Our findings highlight the important role of immune cells after stroke and the therapeutic relevance of their polarization balance.Electronic supplementary materialThe online version of this article (doi:10.1007/s11481-016-9700-y) contains supplementary material, which is available to authorized users.

Meisoindigo Protects Against Focal Cerebral Ischemia-Reperfusion Injury by Inhibiting NLRP3 Inflammasome Activation and Regulating Microglia/Macrophage Polarization via TLR4/NF-κB Signaling Pathway

“…The inflammatory response that follows the initial ischemic insult is a key mechanism of secondary degeneration (Jin et al, 2010;Hamzei Taj et al, 2016). The critical roles of the NLRP3 inflammasome during stroke have been documented in many studies (Lepore et al, 2018; FIGURE 9 | Meisoindigo treatment suppresses the activation of the TLR-4/NF-κB/NLRP3 signaling pathway after stroke.…”

“…After ischemic stroke, the resident microglia and circulating macrophages are activated and recruited to the damaged area to clear debris and initiate reparative processes (Zhao et al, 2015;Cai et al, 2018). Interestingly, the activated microglia/macrophages exert dual contrasting effects on CNS injury and recovery, which are related to their two distinct phenotypes (Hu et al, 2012;Liu et al, 2013;Hamzei Taj et al, 2016). Numerous studies show that microglia/macrophages are highly plastic cells (Kigerl et al, 2009;Cai et al, 2018) that can acquire diverse phenotypes and functions in response to specific cues.…”

Environmental Cues Modulate Microglial Cell Behavior Upon Shiga Toxin 2 From Enterohemorrhagic Escherichia coli Exposure

“…On the contrary, HS treatment attenuated MG cells phagocytic profile when combine with LPS. Phagocytic status is not only an activated MG cell feature but also a spillover effect to regulate system homeostasis, conferring MG cells a neuroprotective function through dying cells clearance, preventing pro-inflammatory and neurotoxic molecules events (Hamzei Taj et al, 2016;Wolf et al, 2017;Janda et al, 2018). It has been showed that MG cells phagocytosis impairment worsens Alzheimer Disease pathology (Noda and Suzumura, 2012).…”

Modulators of microglia activation and polarization in ischemic stroke (Review)

“…miRNA-124 is the most abundant mirna present in the CNS and is involved extensively in neuroprotective mechanisms (108,109). in fact, it has been identified to regulate microglia activation and polarization in ischemic stroke (99,110). a previous study demonstrated that miRNA-124 induced neuroprotection and functional improvement through regulating M2 microglia polarization in ischemic stroke (99); upon injection of miRNA-124 into the mouse ipsilateral hemisphere, the number of M2 microglia/macrophages was markedly increased, contributing to neuronal survival by releasing the trophic factor arg-1 following Mcao.…”