The Role of the Mammalian Target of Rapamycin in Microglial Phenotypic Polarization

Abstract

Highlights What are the main findings? mTOR signaling regulates microglial phenotypic plasticity by coordinating many cellular processes including metabolic reprogramming, inflammatory mediator production, and cytoskeletal remodeling. mTORC1 generally amplifies pro-inflammatory microglial responses, whereas mTORC2 appears to promote anti-inflammatory programs in a context-dependent manner. What are the implications of the main findings? The coordination of mTORC1 and mTORC2 signaling may determine microglial states. mTOR modulation may be a therapeutic target for neuroinflammatory diseases. Abstract Microglia are adaptive immune cells that maintain central nervous system homeostasis and respond dynamically to injury, infection, and other neurological insults. While traditionally classified into resting, pro-inflammatory “M1”, and anti-inflammatory “M2” states, advances in multi-omic profiling technologies have established that microglial phenotypes exist along a multidimensional and context-dependent continuum. The mammalian target of rapamycin (mTOR), a central regulator of cellular metabolism, growth, survival, and protein synthesis, has emerged as a potential central mediator of these state transitions through distinct activities downstream of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). In this review, we examine current evidence linking mTOR signaling to microglial phenotypic polarization and functional plasticity. Generally, evidence suggests that mTORC1 acts as a context-dependent amplifier of inflammatory responses, whereas mTORC2 promotes anti-inflammatory and neuroprotective programs; however, the effects of either complex vary according to disease context. Understanding the balance and coordination of mTORC1 and mTORC2 signaling programs may clarify mechanisms that underly chronic neuroinflammation and guide the development of targeted therapies for neuroinflammatory disorders including Alzheimer’s disease, stroke, and epilepsy.