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Cited by 323Autophagy in Disease and TherapyNeuroinflammation and Neurodegeneration MechanismsGenetics, Aging, and Longevity in Model Organisms

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Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

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Plaza-Zabala, Ainhoa, Sierra-Torre, Virginia, Sierra, Amanda·2017·International Journal of Molecular Sciences
DOI 10.3390/ijms18030598PMC PMC5372614
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Abstract

Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health and survival. However, we propose that the (dys)regulation of autophagy in microglia also affects innate immune functions such as phagocytosis and inflammation, which in turn contribute to the pathophysiology of aging and neurodegenerative diseases. Herein, we first describe the basic concepts of autophagy and its regulation, discuss key aspects for its accurate monitoring at the experimental level, and summarize the evidence linking autophagy impairment to CNS senescence and disease. We focus on acute, chronic, and autoimmunity-mediated neurodegeneration, including ischemia/stroke, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and multiple sclerosis. Next, we describe the actual and potential impact of autophagy on microglial phagocytic and inflammatory function. Thus, we provide evidence of how autophagy may affect microglial phagocytosis of apoptotic cells, amyloid-β, synaptic material, and myelin debris, and regulate the progression of age-associated neurodegenerative diseases. We also discuss data linking autophagy to the regulation of the microglial inflammatory phenotype, which is known to contribute to age-related brain dysfunction. Overall, we update the current knowledge of autophagy and microglia, and highlight as yet unexplored mechanisms whereby autophagy in microglia may contribute to CNS disease and senescence.

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Figure 1 Autophagy and phagocytosis are lysosomal clearance pathways that share mechanistic and functional similarities. In response to cellular stress, autophagy (purple flow) is activated by signals that inhibit mechanistic target of rapamycin complex 1 (MTORC1) and activate unc-51 like autophagy activating kinase 1 (ULK-1), whereas phagocytosis (blue flow) is activated by extracellular ligands that bind to phagocytosis receptors in the surface of the microglial plasma membrane. Then, cargo engulfment structures start to form: the phagophore is de novo formed using the endoplasmic reticulum (ER) as a membrane source (autophagy) and the phagocytic cup is formed from invaginations of the plasma membrane (phagocytosis). These structures elongate and close up, forming the double-membrane-bound autophagosome (autophagy) and the single-membrane-containing phagosome (phagocytosis), which contain intracellular and extracellular degradative substrates, respectively. The formation of the autophagosome depends on the sequential and coordinated action of autophagy-related (ATGs) proteins, including microtubule-associated light chain 3 (LC3). In contrast, the formation of the phagosome may depend on the recruitment of autophagy machinery (ATGs and LC3) during LC3-associated phagocytosis (LAP) (described in peripheral macrophages, but not microglia; red question mark in the figure), or may be completed independently of ATGs in other types of phagocytosis. Finally, the autophagosome (autophagy) and the phagosome (phagocytosis), which contain the degradative cargo on their lumen, progressively mature and fuse with lysosomes, forming the autophagolysosome and the phagolysosome, respectively, where the cargo is finally digested. Autophagy and phagocytosis may serve similar functions in microglia, including the supply of energy during nutrient shortage, maintenance of cellular and tissue homeostasis, and the promotion of a net anti-inflammatory phenotype (see main text for details).
Figure 1 Autophagy and phagocytosis are lysosomal clearance pathways that share mechanistic and functional similarities. In response to cellular stress, autophagy (purple flow) is activated by signals that inhibit mechanistic target of rapamycin complex 1 (MTORC1) and activate unc-51 like autophagy activating kinase 1 (ULK-1), whereas phagocytosis (blue flow) is activated by extracellular ligands that bind to phagocytosis receptors in the surface of the microglial plasma membrane. Then, cargo engulfment structures start to form: the phagophore is de novo formed using the endoplasmic reticulum (ER) as a membrane source (autophagy) and the phagocytic cup is formed from invaginations of the plasma membrane (phagocytosis). These structures elongate and close up, forming the double-membrane-bound autophagosome (autophagy) and the single-membrane-containing phagosome (phagocytosis), which contain intracellular and extracellular degradative substrates, respectively. The formation of the autophagosome depends on the sequential and coordinated action of autophagy-related (ATGs) proteins, including microtubule-associated light chain 3 (LC3). In contrast, the formation of the phagosome may depend on the recruitment of autophagy machinery (ATGs and LC3) during LC3-associated phagocytosis (LAP) (described in peripheral macrophages, but not microglia; red question mark in the figure), or may be completed independently of ATGs in other types of phagocytosis. Finally, the autophagosome (autophagy) and the phagosome (phagocytosis), which contain the degradative cargo on their lumen, progressively mature and fuse with lysosomes, forming the autophagolysosome and the phagolysosome, respectively, where the cargo is finally digested. Autophagy and phagocytosis may serve similar functions in microglia, including the supply of energy during nutrient shortage, maintenance of cellular and tissue homeostasis, and the promotion of a net anti-inflammatory phenotype (see main text for details).CC BY · PubMed Central
Figure 2 Autophagy may negatively regulate microglial inflammation: potential mechanisms of inflammasome regulation. Inflammasomes are cytosolic macromolecular sensors that assemble after activation by infectious or damaging stimuli (illustrated by blue arrows). They consist of a ligand sensor (i.e., NLRP3), an adaptor protein (ASC), and the immature form of the inflammatory caspase, pro-caspase-1. Inflammasome assembly induces the proteolytic processing of pro-caspase-1 to its active form caspase-1. Subsequently, activated caspase-1 proteolytically processes the immature forms of inflammatory cytokines pro-IL-1β and pro-IL-18 to active inflammatory mediators IL-1β and IL-18. In peripheral macrophages, three types of modulatory interactions have been described to explain the suppresive effect of autophagy over the inflammasome (illustrated by purple arrows). Thus, autophagy may target (1) the inflammasome adaptor protein ASC and/or (2) the inflammasome substrate pro-IL-1β for digestion to the lysosome. On the other hand, autophagy may (3) selectively digest damaged, ROS-generating mitochondria by mitophagy. Note that none of these mechanisms have yet been described in microglia (see main text for details).
Figure 2 Autophagy may negatively regulate microglial inflammation: potential mechanisms of inflammasome regulation. Inflammasomes are cytosolic macromolecular sensors that assemble after activation by infectious or damaging stimuli (illustrated by blue arrows). They consist of a ligand sensor (i.e., NLRP3), an adaptor protein (ASC), and the immature form of the inflammatory caspase, pro-caspase-1. Inflammasome assembly induces the proteolytic processing of pro-caspase-1 to its active form caspase-1. Subsequently, activated caspase-1 proteolytically processes the immature forms of inflammatory cytokines pro-IL-1β and pro-IL-18 to active inflammatory mediators IL-1β and IL-18. In peripheral macrophages, three types of modulatory interactions have been described to explain the suppresive effect of autophagy over the inflammasome (illustrated by purple arrows). Thus, autophagy may target (1) the inflammasome adaptor protein ASC and/or (2) the inflammasome substrate pro-IL-1β for digestion to the lysosome. On the other hand, autophagy may (3) selectively digest damaged, ROS-generating mitochondria by mitophagy. Note that none of these mechanisms have yet been described in microglia (see main text for details).CC BY · PubMed Central

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  1. Monti, 2016, Inflammaging and omics in human longevity, Mech. Ageing Dev., 6374, 30261

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Metadata

Authors
Plaza-Zabala, A., Sierra-Torre, V., & Sierra, A.
Affiliations
  • Achucarro Basque Center for Neuroscience, 48170 Zamudio, Spain
  • Ikerbasque (ES)
Corresponding author
Sierra, Amanda
ORCID
Sierra, Amanda
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2017-03-09
Volume
18
Issue
3
Pages
598
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms18030598
PMC
PMC5372614
OpenAlex
W2594094135
Cited by
323
References
169
Citations by year
2026: 23 · 2025: 24 · 2024: 25 · 2023: 42 · 2022: 37 · 2021: 55 · 2020: 38 · 2019: 39 · 2018: 32 · 2017: 8
FWCI
4.24
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Spanish Ministry of Economy and Competitiveness (BFU2015-66689, RYC-2013-12817)
  • BBVA Foundation Grant for Researchers and Cultural Creators
  • Basque Government (PI_2016_1_0011)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
autophagy, microglia, neurodegeneration, brain aging, microglial phagocytosis, neuroinflammation, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyloid-beta clearance, myelin debris, autophagy regulation, autophagy monitoring
MeSH terms
Aging, Animals, Autophagy, Central Nervous System, Humans, Microglia, Neurodegenerative Diseases

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