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Linking Impaired Autophagy to Changes in Polarization of Microglia in Aging

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Posted 12 December 2018 - 11:22 AM

The polarization of the immune cells known as macrophages and microglia is a topic of growing interest in the study of aging and age-related disease. A perhaps overly simplistic summary is that polarization describes the state and preferred activities of a macrophage or microglial cell, changing in response to signals and environment. The states of greatest interest are M1, inflammatory and aggressive in pursuit of pathogens, versus M2, a helper in tissue maintenance and regeneration. Both polarizations are necessary in the grand scheme of things, but in older individuals and in tissues affected by age-related disease, a an excess of M1 macrophages or microglia is a common theme. The result is a diminished capacity for regeneration and necessary processes of maintenance.

Too great a number of M1 polarized cells ties in to the chronic inflammation of aging, as inflammatory signals provoke macrophages into this polarization. In this context, researchers are investigating a range of possible strategies to override polarization, forcing immune cells back into the M2 state. Another aspect of this issue is added here in an open access paper linking the quality of autophagy to polarization. Autophagy is the name given to a collection of cell maintenance processes responsible for breaking down and recycling damaged structures and proteins. That it would be linked to immune cell polarization is most interesting, as autophagic activity is known to decline with age. Increased autophagy is associated with increased longevity in a variety of interventions examined in laboratory species, such as calorie restriction. It remains to be seen how strong this relationship is in comparison to the relationship with inflammation, but it seems that they influence one another, and are not independent.

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 expression and reduction of M2 marker expression 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 with Atg5 knockdown in cells, but alleviated given microglia pretreatment with rapamycin, suggesting that activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation. 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.

Link: https://doi.org/10.3...nagi.2018.00378

View the full article at FightAging

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