Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

Abstract

Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either detrimental or beneficial effects in the central nervous system (CNS). Harnessing the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of Parkinson's disease (PD). However, the epigenetic mechanism that regulates microglia polarization remains elusive. Here, we reported that histone H3K27me3 demethylase Jumonji domain containing 3 (Jmjd3) was essential for M2 microglia polarization. Suppression of Jmjd3 in N9 microglia inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, which led to extensive neuron death in vitro. We also observed that the suppression of Jmjd3 in the substantia nigra (SN) in vivo dramatically caused microglial overactivation and exacerbated dopamine (DA) neuron death in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD. Moreover, we showed that the Jmjd3 level was lower in the midbrain of aged mice, which was accompanied by an elevated level of H3K27me3 and an increased ratio of M1 to M2 markers, suggesting that aging is an important factor in switching the microglia phenotypes. Overall, our studies indicate that Jmjd3 is able to enhance the polarization of M2 microglia by modifying histone H3K27me3, and therefore it has a pivotal role in the switch of microglia phenotypes that may contribute to the immune pathogenesis of PD.

Microglia and Monocyte-Derived Macrophages in Stroke

“…Basal and stimulated secretion of TNF-α and IL-6 were increased in the ex vivo culture of senescent microglia [203], and hypertrophic morphological changes in the aged cells were observed [197,204,205]. Consistent with this evidence, an in vivo study showed that iNOS, TNF-α, and IL-6 were elevated, while arginase-1 was repressed in the midbrain of aged mice [206]. In contrast, peripheral macrophages exhibited less classical activation, leading to an attenuated proinflammatory response [207].…”

Activation of murine microglial N9 cells is attenuated through cannabinoid receptor CB2 signaling

“…: no significance. microglial M1 and M2 states, such as iNOS, TNF-a, IL-1b and Arg-1, in the presence of stimulus [26,27]. Thus, we used N9 microglia to study microglial M1 and M2 states in this investigation.…”

G2019S LRRK2 and aging confer susceptibility to proteasome inhibitor-induced neurotoxicity in nigrostriatal dopaminergic system

“…A number of biological processes could be affected by aging including the ability of mitochondria to handle with calcium, the iron level within neurons, the function of UPS and the activating pattern of microglia and, etc. (Crain et al 2013;Reeve et al 2014;Tang et al 2014). Understandably, these functional changes might weaken the nigral DAergic neurons, rendering the neurons more vulnerable to additional insults (Reeve et al 2014).…”