M2 Phenotype Microglia-derived Cytokine Stimulates Proliferation and Neuronal Differentiation of Endogenous Stem Cells in Ischemic Brain

Abstract

Microglia play a key role in the immune response and inflammatory reaction that occurs in response to ischemic stroke. Activated microglia promote neuronal damage or protection in injured brain tissue. Extracellular signals polarize the microglia towards the M1/M2 phenotype. The M1/M2 phenotype microglia released pro- and anti-inflammatory cytokines which induce the activation of neural stem/progenitor cells (NSPCs). In this study, we investigated how the cytokines released by microglia affect the activation of NSPCs. First, we treated BV2 cells with a lipopolysaccharide (LPS; 20 ng/ml) for M1 phenotype microglia and interleukin-4 (IL-4; 20 ng/ml) for M2 phenotype microglia in BV2 cells. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 1 h. In ex vivo, brain sections containing the subventricular zone (SVZ) were cultured in conditioned media of M1 and M2 phenotype-conditioned media for 3 d. We measured the expression of cytokines in the conditioned media by RT-PCR and ELISA. The M2 phenotype microglia-conditioned media led to the proliferation and neural differentiation of NSPCs in the ipsilateral SVZ after ischemic stroke. The RT-PCR and ELISA results showed that the expression of TGF-α mRNA was significantly higher in the M2 phenotype microglia-conditioned media. These data support that M2 phenotype microglia-derived TGF-α is one of the key factors to enhance proliferation and neural differntiation of NSPCs after ischemic stroke.

Interferon regulatory factor 4/5 signaling impacts on microglial activation after ischemic stroke in mice

“…Therefore, M1 or M2 phenotype is not ‘pure’ but rather reflects the predominant inflammatory state of microglia after an ischemic insult. IRF5/4 regulatory axis may regulate the dynamic balance between M1 and M2 microglial states, and the two phenotypes evolve and transition into each other during the disease progression (Giunti et al ., ; Choi et al ., ).…”

Acute exposure to diesel exhaust impairs adult neurogenesis in mice: prominence in males and protective effect of pioglitazone

“…It should be noted that microglia may either promote or inhibit adult neurogenesis (Sato 2015), depending on the activation state (Aarum et al 2003; Xu et al 2017). Notably, the M2 activation state, which is induced by anti-inflammatory cytokines such as IL-4, favors proliferation, and can direct neural progenitor cells (NPC) towards neurogenesis (Cherry et al 2014; Choi et al 2017; Zhao et al 2017). In contrast, the inflammatory cytokines such as interferon-γ and TNFα, as well as oxidative stress, induce the M1 (classical activation) state, provoking killing behavior in microglia and other macrophages (Colton 2009).…”

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

“…Zhu et al (25) observed that M2 microglia-induced chitinase-3-like protein 3 (Ym1/2), il-10 and transforming growth factor-β (TGF-β) secretion promoted angiogenesis, and thereby decreased the BBB leakage and improved stroke outcome. in addition, choi et al (53) confirmed that M2 microglia promoted the proliferation and neuronal differentiation of neural stem/progenitor cells in the ipsilateral subventricular zone following ischemic stroke through upregulating the expression levels of TGF-α; this may provide an effective therapy for neurogenesis. additionally, macrophages recruited by microglia were identified to enhance M2 microglia polarization and improve stroke outcome (54,55).…”