RESUMEN
Pulmonary fibrosis is a devastating disorder distinguished by redundant inflammation and matrix accumulation in the lung interstitium. The early inflammatory cascade coupled with recurring tissue injury orchestrates a set of events marked by perturbed matrix hemostasis, deposition of matrix proteins, and remodeling in lung tissue. Numerous investigations have corroborated a direct correlation between the NLR family pyrin domain-containing 3 (NLRP3) activation and the development of pulmonary fibrosis. Dysregulated activation of NLRP3 within the pulmonary microenvironment exacerbates inflammation and may incite fibrogenic responses. Nevertheless, the precise mechanisms through which the NLRP3 inflammasome elicits pro-fibrogenic responses remain inadequately defined. Contemporary findings suggest that the pro-fibrotic consequences stemming from NLRP3 signaling primarily hinge on the action of interleukin-1ß (IL-1ß). IL-1ß instigates IL-1 receptor signaling, potentiating the activity of transforming growth factor-beta (TGF-ß). This signaling cascade, in turn, exerts influence over various transcription factors, including SNAIL, TWIST, and zinc finger E-box-binding homeobox 1 (ZEB 1/2), which collectively foster myofibroblast activation and consequent lung fibrosis. Here, we have connected the dots to illustrate how the NLRP3 inflammasome orchestrates a multitude of signaling events, including the activation of transcription factors that facilitate myofibroblast activation and subsequent lung remodeling. In addition, we have highlighted the prominent role played by various cells in the formation of myofibroblasts, the primary culprit in lung fibrosis. We also provided a concise overview of various compounds that hold the potential to impede NLRP3 inflammasome signaling, thus offering a promising avenue for the treatment of pulmonary fibrosis.
Asunto(s)
Inflamasomas , Fibrosis Pulmonar , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Inflamación , Factores de TranscripciónRESUMEN
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-1ß, 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.