Ischemic stroke (IS), is caused by a transient or permanent reduction in local cerebral blood flow, leading to downstream tissue hypoxia and inadequate glucose supply(Zhang et al., 2016), resulting in brain tissue damage. Under the influence of ischemic and hypoxic conditions, nerve cells initiate the release of damage-associated molecular patterns (DAMPs), cytokines, and chemokines(Dirnagl et al., 1999), leading to protein and lipid lism disorders, dysfunction of ion pumps, membrane depolarization, Ca2+ imbalance, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and activation of microglia(Lin et al., 2021; Wang et al., 2020c; Li et al., 2020c), all of which contribute to the inflammatory processes following stroke.

Microglia are innate immune cells in the brain. Following ischemic stroke, damaged brain cells activate DAMPs and release factors such as LPS, TNF-α, and IFN-γ(Nakagawa and Chiba, 2015), which activate microglia. Peripheral macrophages are also recruited to participate in the pathological process following ischemic stroke(Lyu et al., 2021). In brain tissue, CD11b and CD45 combination labeling can be used to distinguish between microglia and macrophages. Resting microglia have surface markers of CD11bhi and CD45low, while macrophages have CD11bhi and CD45hi(Perego et al., 2011). The polarization of microglia induced by ischemic hypoxic injury is mainly divided into two types. M1 microglia, known as "pro-inflammatory phenotype," release pro-inflammatory mediators including IL-6, TNF-α, iNOS, COX2, exacerbating neural damage. On the other hand, interleukin-4 (IL-4), interleukin-10 (IL-10), transforming growth factor-β (TGF-β) and other factors promote the transformation of microglia into the M2 phenotype, leading to the secretion of anti-inflammatory factors and growth-promoting factors, thus reducing the loss of nerve function after stroke(Nakagawa and Chiba, 2015). The dynamic changes of microglial polarization are still debated, but it is generally believed that the M2 microglia appear early in the onset of stroke and their numbers gradually increase, but start to decrease around 3 days later. On the other hand, the M1 microglia show a persistent increase after stroke, and in the middle and late stages, they become the predominant type(Lyu et al., 2021; Perego et al., 2011).

Polarization is the major change in microglia following ischemic stroke, but alterations in other functional phenotypes of microglia also have a significant impact on the prognosis of ischemic stroke. Under the influence of hypoxia and inflammatory conditions, microglia undergo autophagy, in which autophagosomes clear and recycle damaged intracellular organelles and misfolded proteins (Dikic and Elazar, 2018), to avoid the release of reactive oxygen species and various inflammatory mediators leading to further tissue damage, the degraded components are converted into small molecular materials for cellular utilization, promoting cell survival (Mugume et al., 2020). In addition, certain metabolic waste products released by ischemic-hypoxic damaged neurons, such as dead cells, aggregated proteins, and cellular debris, are primarily cleared through phagocytic activity of microglia to prevent the release of reactive oxygen species and various inflammatory mediators that may cause further tissue damage(Wolf et al., 2017). Cell pyroptosis, as a novel form of cell death, can also occur in the pathological process of ischemic stroke. Under the joint stimulation of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs)(Xu et al., 2019), the process of microglial pyroptosis is initiated. The cells swell and the cell membrane ruptures, leading to the release of cellular contents, thereby activating a strong inflammatory response (Rao et al., 2022), which is closely associated with the activation of NLRP3 inflammasomes. Furthermore, ischemic stroke-induced sterile neuroinflammation can also induce ferroptosis in microglia, which is the rupture of cell membranes caused by lipid peroxidation due to intracellular Fe2+ overload (Jiang et al., 2021). At the same time, intracellular iron accumulation can promote the transformation of microglia to a pro-inflammatory phenotype and exacerbate the detrimental effects of M1 microglia on other neurons (Zhou et al., 2017). The interplay between these processes further exacerbates post-stroke neuronal functional impairment. Apoptosis, as an active programmed cell death form, is also widely observed in microglia following ischemic stroke. Additionally, necrosis, as a pathological cell death process, has been identified in microglia following ischemic stroke.

After ischemic stroke, microglia participate in the process of neuronal damage repair through the regulation of polarization, autophagy, phagocytosis, pyroptosis, and iron-dependent cell death, apoptosis, and necrosis. (Fig. 1). There are intricate relationships between different functional phenotypes of microglia. This article reviews the different functional phenotypes and states of microglia after stroke, aiming to provide clues for improving neuroinflammation, reducing brain tissue damage, minimizing complications, and improving patient prognosis(Xu et al., 2021; Zhang et al., 2021).