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Loss of Autophagy Linked to Changes in Microglia


Researchers have discovered a link between the cellular recycling system known as autophagy and the behavior of microglial immune cells during aging.

The polarization of macrophages

We have discussed the polarization of macrophages in a number of previous articles, and it has become quite a hot topic among researchers in the last few years. Microglia are tissue-resident macrophages in the central nervous system, and, like other macrophages, they also have a certain polarization state that essentially determines their behavioral patterns and activities.

There are two main polarizations in macrophages that are of interest: M1 and M2. In simple terms, M1 macrophages aggressively intercept pathogens and are proinflammatory, as they use various cellular weapons against invading bacteria and viruses. In contrast, M2 macrophages are focused on reducing inflammation to facilitate tissue repair and healing.

Under normal conditions, both polarizations are needed to maintain defenses and keep tissue healthy; however, during aging, the ratio of M1 to M2 microglia (and other macrophages elsewhere in the body) becomes unbalanced and tips towards inflammatory M1 rather than healing M2. Polarization is guided by the local environment, and inflammatory signals guide macrophages towards the M1 type. This means that as we age and our chronic inflammation increases, more and more macrophages, including microglia, shift towards this M1 profile.

Cell polarization influences autophagy

A new study adds another part to the polarization story and shows the link between the level of autophagy in the cell and its polarization. Autophagy is the collective name given to cellular processes that break down and recycle proteins and other structures, and its activity declines during aging. Neuroinflammation and the decline of autophagy are associated with the development of neurodegenerative diseases such as Parkinson’s.

These researchers demonstrate that exposure of microglia to TNF-α, a proinflammatory signaling molecule, inhibits autophagy and shifts microglia towards M1 polarization. On the other hand, a shift towards M2 is seen when the autophagy-inducing compounds rapamycin and resveratrol are used.


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.


These results suggest that TNF-α inhibits autophagy in microglia through the AKT/mTOR pathway, which is part of deregulated nutrient sensing, one of the hallmarks of aging. It also suggests that as a potential therapy, increasing autophagy may be beneficial for tissue repair and maintenance.

This builds the case for effective management of age-related inflammation to reduce dysfunction and ties in with the wider topic of inflammaging.

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[1] Jin, M., Wang, F., Liu, W., Qi, D., Gu, C., Mao, C. J., … & Liu, C. F. (2018). A critical Role of autophagy in regulating microglia polarization in neurodegeneration. Frontiers in aging neuroscience, 10, 378.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
  1. December 17, 2018

    Thank you – Your information feed is highly valuable

  2. December 18, 2018

    If only there existed autophagy enhancers that are safer than rapamycin and more potent than resveratrol.

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