Microglia are extra-embryonic yolk sac-derived myeloid cells in the Central Nervous System (CNS) possessing memory-like features to be able to have context-dependent responses (Ginhoux and Prinz 2015). They are distributed throughout the brain and interact with neurons, astrocytes and oligodendrocytes. At first, they were thought to be of neuroectodermal origin (Prinz, Jung et al. 2019). However, it is now determined that they are from myeloid lineage because of expressing several genes unique for myeloid lineage (Dubbelaar, Kracht et al. 2018). Microglial cells participate in immune response and regulate homeostasis of brain through searching for both internal dangers such as damaged tissues or dying cells, and external dangers such as pathogens. When faced with these problems, they start analyzing the injury, reducing the effects of inflammation and participating in tissue repair and remodeling (Ginhoux and Prinz 2015), (Kabba, Xu et al. 2018).
Microglia History and Origin
Microglia were distinguished as a divergent and privatized myeloid cells of CNS with characteristic developmental source via taking for more than 150 years of research (Ginhoux and Prinz 2015). For the first time in 1932, Del Rio-Hortega described a population of phagocytic and migratory cells that are in the CNS and of mesodermal origin. He first established the term ‘microglial cell’ in 1939 and identified them as non-neuronal, non-astrocytic agents of CNS and apart from astrocytes, oligodendrocytes and macroglia (Kettenmann, Hanisch et al. 2011), (Ginhoux and Prinz 2015), (Kabba, Xu et al. 2018). Over the years with debates about the origin of microglia whether it is mesodermal or ectodermal, several researchers proved their mesodermal origin with studies coupling light/electron microscopy and immunohistochemistry (Ginhoux and Prinz 2015).
Microglia Activation States
Activation states of microglia is classified as M1 (classical) and M2 (alternative). M1 state is pro-inflammatory and neurotoxic that is induced via stimulating both Toll-like receptor (TLR) and interferon (IFN)-γ pathways (Colonna and Butovsky 2017). At this state, microglia generate proinflammatory cytokines and chemokines like interleukin (IL)-6, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interleukin (IL)-12 and C-C Motif Chemokine Ligand 2 (CCL2) (Dubbelaar, Kracht et al. 2018). M1 microglia also generates reactive oxygen species (ROS), nitric oxide (NO), matrix metalloproteinase 12 (MMP12), major histocompatibility complex (MHC) II, Fc receptors and integrins. On the other hand, M2 state is anti-inflammatory and induces release of IL-10 and transforming growth factor (TGF)-β, and has the capacity to enable debris clearance, wound healing and recover brain tissue homeostasis (Dubbelaar, Kracht et al. 2018). M2 microglia is stimulated via IL-4, IL-13, etc., and secretes growth factors and neurotrophic factors (Colonna and Butovsky 2017).
Microglia have several functions including wiring of the brain in early development and involving in homeostasis over the course of life (Sominsky, De Luca et al. 2018). In early stages, activated microglia participate in neuroprotection, while in later stages, it participates in neuroinflammation and neurodegeneration (Petralla, De Chirico et al. 2021). Very early in development, microglia support synaptogenesis and dendritic spine generation via releasing relevant growth factors such as prostaglandin E2 and IL-10 (Lenz and Nelson 2018), and this support is important for behaviour (Sominsky, De Luca et al. 2018). In the developing central nervous system (CNS), microglia adjust brain improvement mainly by phagocytosis and releasing diffusible factors (Lenz and Nelson 2018) such as tumor necrosis factor (TNF) and nerve growth factor (NGF) (Matejuk and Ransohoff 2020). Microglia induce and promote cell formation and health through releasing insulin-like growth factor 1 (IGF1), tumor necrosis factor (TNF)-α and interferon (IFN)-γ. Living, dying or dead cells, axons and synaptic elements are phagocytosed by microglia. Several agents participate in microglia phagocytosis like vascular endothelial growth factor (VEGF), NADPH oxidase (Nox) 2 and Tyrobp/DAP12 either via identifying cells signed for scavencing or stimulating cell demise. Microglial cells also promote neurogenesis, axon twitch myelination/oligodendrogenesis, cell demise or cell survival, and excite synaptogenesis and synapse ageing (Lenz and Nelson 2018).