A richer and more diverse future for microglia phenotypes

Abstract

Microglia are the only resident innate immune cells derived from the mesoderm in the nerve tissue. They play a role in the development and maturation of the central nervous system (CNS). Microglia mediate the repair of CNS injury and participate in endogenous immune response induced by various diseases by exerting neuroprotective or neurotoxic effects. Traditionally, microglia are considered to be in a resting state, the M0 type, under physiological conditions. In this state, they perform immune surveillance by constantly monitoring pathological responses in the CNS. In the pathological state, microglia undergo a series of morphological and functional changes from the M0 state and eventually polarize into classically activated microglia (M1) and alternatively activated microglia (M2). M1 microglia release inflammatory factors and toxic substances to inhibit pathogens, while M2 microglia exert neuroprotective effects by promoting nerve repair and regeneration. However, in recent years, the view regarding M1/M2 polarization of microglia has gradually changed. According to some researchers, the phenomenon of microglia polarization is not yet confirmed. The M1/M2 polarization term is used for a simplified description of its phenotype and function. Other researchers believe that the microglia polarization process is rich and diverse, and consequently, the classification method of M1/M2 has limitations. This conflict hinders the academic community from establishing more meaningful microglia polarization pathways and terms, and therefore, a careful revision of the concept of microglia polarization is required. The present article briefly reviews the current consensus and controversy regarding microglial polarization typing to provide supporting materials for a more objective understanding of the functional phenotype of microglia.

Keywords: M1/M2 subtype; Microglia; Multiple subtypes; Polarization.

Fig. 1

Morphological changes in microglia before and after polarization. A: Microglia in the unactivated state of growth in good condition, with a clear background. The cell body is small and occasionally observed between cell synaptic connections. The microglial cell has a full three-dimensional shape with fewer branches. B: After activation, microglia cell debris increased. The background is not clear; with an increase in the size of the cell body, the emergence of “amoeba-like cells,” increased synaptic connections between the cell bodies, and increased branches.

Fig. 2

Microglia polarization diagram: M1 microglia release pro-inflammatory factors and toxic substances to kill pathogens, while M2 microglia exert neuroprotective effects by promoting tissue repair and regeneration. Overactivated M1 microglia can cause neuronal disability, damage, and degeneration and play an important role in cerebrovascular diseases, neurodegenerative diseases, neurodevelopmental disorders, and mental disorders.

Fig. 3

Microglia activation and inactivation diagram: Resting microglia are constantly in an “immune surveillance” state. After stimulation, microglia convert to an activated state and then return again to the resting state. Following stimulation, microglial cells change their morphological appearance and become “amoeba-like” glial cells, which respond to external stimuli, play an immunological role, and then return to the resting state. Some microglial cells are inactivated and die during the immune response.