The role of autophagy and macrophage polarization in the processes of chronic inflammation and regeneration

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Abstract

The cause of many serious illnesses, including diabetes, obesity, osteoporosis and neurodegenerative diseases is chronic inflammation that develops in adipose tissue, bones or the brain. This inflammation occurs due to a shift in the polarization of macrophages/microglia towards the pro-inflammatory phenotype M1. It has now been proven that the polarization of macrophages is determined by the intracellular level of autophagy in the macrophage. By modulating autophagy, it is possible to cause switching of macrophage activities towards M1 or M2. Summarizing the material accumulated in the literature, we believe that the activation of autophagy reprograms the macrophage towards M2, replacing its protein content, receptor apparatus and including a different type of metabolism. The term reprogramming is most suitable for this process, since it is followed by a change in the functional activity of the macrophage, namely, switching from cytotoxic pro-inflammatory activity to anti-inflammatory (regenerative). Modulation of autophagy can be an approach to the treatment of oncological diseases, neurodegenerative disorders, osteoporosis, diabetes and other serious diseases.

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About the authors

S. G. Zubova

Institute of Cytology of the Russian Academy of Sciences

Author for correspondence.
Email: egretta_julia@mail.ru
Russian Federation, St. Petersburg

A. V. Morshneva

Institute of Cytology of the Russian Academy of Sciences

Email: egretta_julia@mail.ru
Russian Federation, St. Petersburg

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2. Fig. 1. Illustration of classical M1 (pro-inflammatory) and alternative M2 (anti-inflammatory) activation of macrophages. Rapamycin is an immunosuppressant derived from Streptomyces hygroscopicus, an autophagy activator (AF), its target is the kinase protein complex mTORC1; resveratrol is a natural phytoalexin, an autophagy activator: chloroquine is a drug from the 4-aminoquinoline group, an autophagy inhibitor, blocks autophagosome to lysosome binding. The pro-inflammatory phenotype of macrophages is characterized by glycolysis, while the anti-inflammatory phenotype is characterized by oxidative phosphorylation. Classically activated macrophages secrete proinflammatory cytokines (IL6, IL1α, IL1β, IL12, TNFα) upon receptor activation, particularly to lipopolysaccharide (LPS) and IFNγ. Classically activated macrophages synthesize reactive oxygen species (ROS). Alternatively, activated macrophages secrete anti-inflammatory cytokines (IL4, IL10, IL12, TGFβ) upon receptor activation, e.g. to IL4, IL13, IL10

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3. Fig. 2. Autophagy regulatory pathways. Autophagy (AF) is activated in the absence of growth factors, such as under starvation conditions. AF is inhibited by enhanced growth factor signaling through the PI3 group of class I and Akt kinases to stimulate mTORC1 activity by inhibiting the TSC1/TSC2 complex and increasing Rheb GTPase activity. The process of AF begins with phagophore formation. It is negatively regulated by the serine-threonine specificity protein kinase mTORC1. Under nutrient deficiency, mTORC1 dissociates from the ULK1 complex, and ULK1 is activated and phosphorylates FIP200, which triggers phagophore formation; a preinitiator complex consisting of ULK1, FIP200, and Atg13 is formed. Assembly of this complex is required for activation of the initiation complex (Beclin 1, VPS15 and VPS34, which generates PI3P and recruits Atg7 to the phagophore surface). This activates two conjugation systems involving Atg family proteins (Atg5, Atg7, Atg10, Atg12, etc.) These protein interactions are required for autophagosome closure and maturation. The LC3-I protein then forms a complex with phosphatidylethanolamine (PE) and generates a form of LC3-II that binds to the outer and inner membrane of the autophagosome. This is required for fusion with the lysosome of the formed autophagosome. The autophagolysosome content is then degraded. In the presence of nutrients, mTORC1 kinase can phosphorylate the transcription factor TFEB and inhibit its activity, but TFEB becomes hypophosphorylated and localizes to the nucleus when nutrient and energy levels are low. While in the nucleus, TFEB activates lysosomal and autophagic genes

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