Microglial pyroptosis: Therapeutic target in secondary brain injury following intracerebral hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a major cerebrovascular illness that causes substantial neurological sequelae and dysfunction caused by secondary brain injury (SBI), and there are no effective therapies to mitigate the disability. Microglia, the brain-resident macrophage, participates in the primary inflammatory response, and activation of microglia to an M1-like phenotype largely takes place in the acute phase following ICH. A growing body of research suggests that the pathophysiology of SBI after ICH is mediated by an inflammatory response mediated by microglial-pyroptotic inflammasomes, while inhibiting the activation of microglial pyroptosis could suppress the inflammatory cascade reaction, thus attenuating the brain injury after ICH. Pyroptosis is characterized by rapid plasma membrane disruption, followed by the release of cellular contents and pro-inflammatory mediators. In this review, we outline the molecular mechanism of microglial pyroptosis and summarize the up-to-date evidence of its involvement in the pathological process of ICH, and highlight microglial pyroptosis-targeted strategies that have the potential to cure intracerebral hemorrhage. This review contributes to a better understanding of the function of microglial pyroptosis in ICH and assesses it as a possible therapeutic target.

Ursolic Acid Alleviates Neuroinflammation after Intracerebral Hemorrhage by Mediating Microglial Pyroptosis via the NF-κB/NLRP3/GSDMD Pathway

“…N-terminal GSDMD can adhere to cells and cause cell perforation [34]. The perforation of microglia leads to an accelerated release of intracellular inflammatory factors, and the leakage of inflammatory factors repeats the above process, leading to an increased neuroinflammatory response [23,35].…”

Activating transcription factor 6 alleviates secondary brain injury by increasing cystathionine γ-lyase expression in a rat model of intracerebral hemorrhage

“…The latter encompasses various pathophysiological processes, such as apoptosis activation, brain tissue ischemia and edema exacerbation around the hematoma, and related toxicities corresponding to these symptoms [8,9]. Multiple studies underscore that neurological deterioration following ICH is mainly induced by secondary rather than primary brain injury [10]. Despite numerous research efforts and clinical trials to develop promising ICH therapies, the resultant mortality remains high, and no effective treatment has significantly improved patient prognosis [11].…”

E3 ligase Nedd4L promotes macrophage M1 polarization and exacerbates brain damage by TRAF3/TBK1 signaling pathway after ICH in mice

“…Among the factors of brain in ammation, macrophage activation plays a vital role in the secondary damage of ICH. Various stimuli, including thrombin or glutamate, activate macrophage and initiate an in ammatory response (7)(8)(9).…”