Modulating monocyte-derived macrophage polarization in cerebral ischemic injury with hyperglycemia

Ischemic stroke (IS) results from abnormal blood flow to the brain and subsequent brain cell damage, and is accompanied by various neurological defects such as hemiplegia and speech disorders. It stands as a leading contributor to morbidity and mortality globally. Cerebral ischemia-reperfusion treatment is used to restore blood flow; however, it results in secondary brain damage, which causes neuroinflammation and oxidative stress (Aronowski et al., 1997; Li et al., 2022).

Recent investigations have sought to explore the connection between hyperglycemia (HG) and IS to clarify the underlying mechanisms and identify potential therapeutic interventions. Approximately 30–40% of acute stroke patients have HG (Uyttenboogaart et al., 2007). Additionally, the prognosis post-stroke is worse. Various studies have demonstrated that vascular injury is associated with abnormal glucose homeostasis, where hyperglycemia increases free radical production and causes blood–brain barrier (BBB) disorders by destroying tight junctions between brain endothelial cells (Yorulmaz et al., 2015).

Consequently, BBB disruption may cause more blood-derived monocytes to enter the brain. Furthermore, hyperglycemia can trigger neuroinflammation and upregulate the expression of pro-inflammatory factors (Morey et al., 2019; Rom et al., 2019), which may affect the phenotypic expression of microglia and monocyte-derived macrophages (MDMs) in ischemic brain tissue, exacerbating neuroinflammation caused by ischemia. Understanding the role of MDMs in neuroinflammation caused by cerebral ischemia is crucial for deciphering the mechanisms and developing therapeutic strategies for IS with HG.

Neuroinflammation is critical in ischemic injury, where reactive oxygen species, cytokines, chemokines, and inflammatory factors induce inflammatory reactions. Resident microglia are known to be rapidly activated post-ischemia (Zheng and Yenari, 2004). In addition to microglia, MDMs play an important role in neuroinflammation after IS. Blood-derived myeloid cells, including monocytes, infiltrate the brain via the damaged BBB (Cha et al., 2022) and are involved in acute inflammatory responses post-ischemia. Monocytes are mobilized to the ischemic parenchyma in the early stage of IS (Chen et al., 2003; Gliem et al., 2012). Additionally, increasing evidence suggests that blood-derived monocytes interact with the surrounding microenvironment, such as activated microglia, and differentiate into pro- or anti-inflammatory macrophages, thereby affecting the prognosis of IS (Breckwoldt et al., 2008). Many researchers have endeavored to identify the effects of microglia and MDMs after IS; however, their exact roles are yet to be determined.

Macrophages have various phenotypes and functions; but can be categorized into two typical phenotypes. The first is the pro-inflammatory phenotype (M1), which causes inflammation by promoting inflammatory factors such as interleukin-1β (IL-1β), interferon-γ (IFN-γ), and inducible nitric oxide synthase (iNOS) (Zheng and Yenari, 2004). The upregulation of surface marker CD80 and CD86 characterizes it. The second is the anti-inflammatory phenotype (M2), which induces tissue recovery and secretion of growth factors. It upregulates arginase 1, CD206, and Ym-1 and produces interleukin-4 (IL-4) and interleukin-13 (IL-13) (Zheng and Yenari, 2004).

Our recent study demonstrated that blood-derived monocytes infiltrate injured tissue during the early phases of stroke and differentiate into M2 macrophages in the mouse brain three days post-ischemia (Park et al., 2021). Furthermore, our findings illustrated that these phenotypic changes of MDMs is mediated by IL-4 and IL-13. HG induces an increased influx of monocyte/macrophages and a pro-inflammatory environment through neuroinflammation and BBB disruption, which may further exacerbate brain injury caused by ischemia. Modulating the phenotypic expressions of these factors may affect the recovery of IS with HG. This study aimed to confirm the effects of modulating phenotypic changes in MDMs on IS under HG conditions and to investigate whether modulating the phenotypical conversion of MDMs by IL-4 and IL-13 affects ischemic injury recovery.

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