A Critical Role of Autophagy in Regulating Microglia Polarization in Neurodegeneration

Abstract

Neuroinflammation and autophagy dysfunction are closely related to the development of neurodegeneration such as Parkinson’s disease (PD). However, the role of autophagy in microglia polarization and neuroinflammation is poorly understood. TNF-α, which is highly toxic to dopaminergic neurons, is implicated as a major mediator of neuroinflammation in PD. In this study, we found that TNF-α resulted in an impairment of autophagic flux in microglia. Concomitantly, an increase of M1 marker (iNOS/NO, IL-1β, and IL-6) expression and reduction of M2 marker (Arginase1, Ym1/2, and IL-10) were observed in TNF-α challenged microglia. Upregulation of autophagy via serum deprivation or pharmacologic activators (rapamycin and resveratrol) promoted microglia polarization toward M2 phenotype, as evidenced by suppressed M1 and elevated M2 gene expression, while inhibition of autophagy with 3-MA or Atg5 siRNA consistently aggravated the M1 polarization induced by TNF-α. Moreover, Atg5 knockdown alone was sufficient to trigger microglia activation toward M1 status. More important, TNF-α stimulated microglia conditioned medium caused neurotoxicity when added to neuronal cells. The neurotoxicity was further aggravated when Atg5 knockdown in BV2 cells but alleviated when microglia pretreatment with rapamycin. Activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation as the AKT specific inhibitor perifosine prevented the increase of LC3II (an autophagic marker) in TNF-α stimulated microglia. Taking together, our results demonstrate that TNF-α inhibits autophagy in microglia through AKT/mTOR signaling pathway, and autophagy enhancement can promote microglia polarization toward M2 phenotype and inflammation resolution.

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

“…In our studies, SR8278 dramatically increased M2 type markers such as CD206 , IL‐10 , and YM1 in vitro as well as in vivo (Figurea d and b), indicating that it may further promote a phagocytic microglial phenotype. Moreover, the previous report suggests that autophagy activation can accelerate M2 microglia polarization under both basal and inflammatory conditions (Jin et al, ), and REV‐ERBs has been linked to regulation of autophagy (Woldt et al, ). From these results, we suspect that SR8278 might induce autophagy by suppressing REV‐ERB function, promoting Aβ clearance and M2‐like polarization.…”

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

“…Inflammatory stimuli which are known to induce the immunoproteasome may impair autophagy activity within either glial cells or neurons. For instance, cytokines such as tumor necrosis factor alpha (TNF-α) impair autophagy flux in microglia, while fostering microglia polarization towards the pro-inflammatory phenotype M1 [223]. Autophagy inhibition exacerbates TNF-α-induced M1 polarization, and remarkably, it is sufficient to trigger microglia activation toward M1 status while producing neurotoxicity [223].…”

“…For instance, cytokines such as tumor necrosis factor alpha (TNF-α) impair autophagy flux in microglia, while fostering microglia polarization towards the pro-inflammatory phenotype M1 [223]. Autophagy inhibition exacerbates TNF-α-induced M1 polarization, and remarkably, it is sufficient to trigger microglia activation toward M1 status while producing neurotoxicity [223]. Conversely, autophagy induction promotes microglia polarization toward the M2 phenotype, thus blunting inflammation and neurotoxicity [223].…”

P2X7R-mediated Autophagic Impairment Contributes to Central Sensitization in a chronic Migraine Model with Recurrent Nitroglycerin Stimulation in Mice

“…However, no studies have examined this mechanism in migraine. It is well documented that autophagic ux can affect the microglial phenotypes and guide the in ammation into a protective or detrimental state [123][124][125][126]. The enhanced autophagy has been reported to induce activation of M1 phenotype microglia and promote the release of pro-in ammatory cytokines.…”