Role of NLRP3 Inflammasome in Stroke Pathobiology: Current Therapeutic Avenues and Future Perspective

Kartik Panbhare, Rukmani Pandey, Chandan Chauhan, Antarip Sinha, Rahul Shukla, Ravinder K. Kaundal

Research output: Contribution to journalReview articlepeer-review

Abstract

Neuroinflammation is a key pathophysiological feature of stroke-associated brain injury. A local innate immune response triggers neuroinflammation following a stroke via activating inflammasomes. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has been heavily implicated in stroke pathobiology. Following a stroke, several stimuli have been suggested to trigger the assembly of the NLRP3 inflammasome. Recent studies have advanced the understanding and revealed several new players regulating NLRP3 inflammasome-mediated neuroinflammation. This article discussed recent advancements in NLRP3 assembly and highlighted stroke-induced mitochondrial dysfunction as a major checkpoint to regulating NLRP3 activation. The NLRP3 inflammasome activation leads to caspase-1-dependent maturation and release of IL-1β, IL-18, and gasdermin D. In addition, genetic or pharmacological inhibition of the NLRP3 inflammasome activation and downstream signaling has been shown to attenuate brain infarction and improve the neurological outcome in experimental models of stroke. Several drug-like small molecules targeting the NLRP3 inflammasome are in different phases of development as novel therapeutics for various inflammatory conditions, including stroke. Understanding how these molecules interfere with NLRP3 inflammasome assembly is paramount for their better optimization and/or development of newer NLRP3 inhibitors. In this review, we summarized the assembly of the NLRP3 inflammasome and discussed the recent advances in understanding the upstream regulators of NLRP3 inflammasome-mediated neuroinflammation following stroke. Additionally, we critically examined the role of the NLRP3 inflammasome-mediated signaling in stroke pathophysiology and the development of therapeutic modalities to target the NLRP3 inflammasome-related signaling for stroke treatment.

Original languageEnglish
Pages (from-to)31-55
Number of pages25
JournalACS Chemical Neuroscience
Volume15
Issue number1
DOIs
StatePublished - 3 Jan 2024

Keywords

  • NLRP3
  • NLRP3 inhibitor
  • Stroke
  • caspase-1
  • inflammasome
  • neuroinflammation

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