Class I PI3K inhibitor ZSTK474 mediates a shift in microglial/macrophage phenotype and inhibits inflammatory response in mice with cerebral ischemia/reperfusion injury

Abstract

BackgroundMicroglia/macrophages play a critical role in the inflammatory and immune processes of cerebral ischemia/reperfusion injury. Since microglia/macrophages can reversibly shift their phenotype toward either a “detrimental” or a “restorative” state in the injured central nervous system (CNS), compounds mediate that shift which could inhibit inflammation and restore the ability to alleviate cerebral ischemia/reperfusion injury would have therapeutic potential.MethodsTransient middle cerebral artery occlusion was induced in male C57BL/6 mice. Mice were randomly separated into a sham-operated group, a control group, and a ZSTK474-treated group. We investigated the effect of ZSTK474 by assessing neurological deficits, infarct volume, and histopathological changes. We then determined the potential mechanism by immunofluorescent staining, quantitative real-time polymerase chain reaction (PCR), and Western blot analysis. The Tukey’s test or Mann–Whitney U test was used to compare differences among the groups.ResultsZSTK474 alleviated neurological deficits and reduced infarct volume in the cerebral ischemia/reperfusion injury model. Presumably, ZSTK474 shifted the phenotype of microglia/macrophages to a restorative state, since this treatment decreased the secretion of pro-inflammatory factors and advanced the secretion of anti-inflammatory factors. These neuroprotective properties of ZSTK474 may be mediated by the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway.ConclusionsZSTK474 can mediate a shift in microglia/macrophage phenotype and inhibit the inflammatory response in cerebral ischemia reperfusion injury of mice. These effects appeared to ensue via the PI3K/AKT/mTORC1 pathway. Therefore, ZSTK474 may represent a therapeutic intervention with potential for circumventing the catastrophic aftermath of ischemic stroke.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0660-1) contains supplementary material, which is available to authorized users.

Microglia Mediated Neuroinflammation: Focus on PI3K Modulation

“…In 2016, Wang and co-workers found that in male C57BL/6 mice ZSTK474, an inhibitor of PI3K had a neuroprotective action because it mitigated cerebral ischemic/reperfusion injury by fostering a beneficial microglial/macrophage phenotype [102].…”

Influenza virus replication in macrophages: balancing protection and pathogenesis

“…Fc receptor-mediated phagocytosis and phagocytic uptake of apoptotic cells is dependent on the activation of phosphoinositide 3-kinase (PI3K) [68]. A PI3K inhibitor decreased expression of CD16 on microglial cells (central nervous system-resident macrophages), suggesting a link between PI3K signalling and Fc receptor expression [69]. Although seasonal H1N1 and H3N2 IAV activate the PI3K signalling pathway in mouse AMs, an H5N1 IAV fails to do the same in infected epithelial cells [70,71].…”

Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway

“…The latter is caused by the rupture of blood vessels, for instance in trauma (3). Cerebral ischemia in strokes blocks delivery of oxygen and nutrients, and the brain has a considerably low tolerance to lack of these substances as it does not store oxygen and glycogen, but has a high oxygen consumption rate and rapid metabolism (4,5). Although rapid restoration of blood supply normalizes the demands for physiological processes, this reperfusion gives rise to other serious problems, such as oxidative stress, inflammatory responses, mitochondrial dysfunction and ion imbalances, which paradoxically antagonize the beneficial effect, resulting in more severe pathological state directly related to the intensity of stroke injury (2).…”