The NLRP3 Inflammasome: An Important Driver of Neuroinflammation in Hemorrhagic Stroke

Abstract

Hemorrhagic stroke is a devastating clinical event with no effective medical treatment. Neuroinflammation, which follows a hemorrhagic stroke, is an important element that involves both acute brain injury and subsequent brain rehabilitation. Therefore, delineating the key inflammatory mediators and deciphering their pathophysiological roles in hemorrhagic strokes is of great importance in the development of novel therapeutic targets for this disease. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multi-protein complex that is localized within the cytoplasm. This NOD-like receptor orchestrates innate immune responses to pathogenic organisms and cell stress through the activation of caspase-1 and the maturation of the proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18. Mounting evidence has demonstrated that when the NLRP3 inflammasome is activated, it exerts harmful effects on brain tissue after a hemorrhagic stroke. This review article summarizes the current knowledge regarding the role and the underlying mechanisms of the NLRP3 inflammasome in the pathophysiological processes of hemorrhagic strokes. A better understanding of the function and regulation of the NLRP3 inflammasome in hemorrhagic strokes will provide clues for devising novel therapeutic strategies to fight this disease.

Keywords: Brain injury; Hemorrhagic stroke; Inflammasome; NLRP3; Neuroinflammation.

Fig. 1

NLRP3 inflammasome in the pathogenesis of hemorrhagic stroke. Whereas a priming signal such as the NF-κB pathway ensures the adequate gene expression of NLRP3, pro-IL 1β, and pro-IL 18 for efficient inflammasome formation, a second signal derived from damage-associated molecular pattern molecules, such as ATP and ROS, can trigger the activation of NLRP3 inflammasome to mediate neuroinflammation in the pathophysiological process of hemorrhagic stroke. The constitutive activation of the NLRP3 inflammasome promotes the processing and secretion of proinflammatory cytokines IL-1β and IL-18, which then leads to the recruitment of other immune cells to the affected brain tissue and results in the amplification of inflammatory responses following a hemorrhagic stroke