Gupta Suman, Cassel Suzanne L, Sutterwala Fayyaz S, Dagvadorj Jargalsaikhan
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Immunol Rev. 2025 Jan;329(1):e13410. doi: 10.1111/imr.13410. Epub 2024 Oct 17.
The NLRP3 inflammasome is a multiprotein complex that upon activation by the innate immune system drives a broad inflammatory response. The primary initial mediators of this response are pro-IL-1β and pro-IL-18, both of which are in an inactive form. Formation and activation of the NLRP3 inflammasome activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 and triggers the formation of gasdermin D pores. Gasdermin D pores allow for the secretion of active IL-1β and IL-18 initiating the organism-wide inflammatory response. The NLRP3 inflammasome response can be beneficial to the host; however, if the NLRP3 inflammasome is inappropriately activated it can lead to significant pathology. While the primary components of the NLRP3 inflammasome are known, the precise details of assembly and activation are less well defined and conflicting. Here, we discuss several of the proposed pathways of activation of the NLRP3 inflammasome. We examine the role of subcellular localization and the reciprocal regulation of the NLRP3 inflammasome by autophagy. We focus on the roles of mitochondria and mitophagy in activating and regulating the NLRP3 inflammasome. Finally, we detail the impact of pathologic NLRP3 responses in the development and manifestations of pulmonary disease.
NLRP3炎性小体是一种多蛋白复合物，在被先天免疫系统激活后会引发广泛的炎症反应。这种反应的主要初始介质是前白细胞介素-1β（pro-IL-1β）和前白细胞介素-18（pro-IL-18），二者均处于无活性形式。NLRP3炎性小体的形成和激活会激活半胱天冬酶-1（caspase-1），后者可切割pro-IL-1β和pro-IL-18，并触发gasdermin D孔道的形成。Gasdermin D孔道允许活性白细胞介素-1β和白细胞介素-18分泌，从而引发全身性炎症反应。NLRP3炎性小体反应对宿主可能有益；然而，如果NLRP3炎性小体被不恰当地激活，则可能导致严重的病理状况。虽然NLRP3炎性小体的主要成分是已知的，但其组装和激活的确切细节仍不太明确且存在争议。在此，我们讨论几种提出的NLRP3炎性小体激活途径。我们研究亚细胞定位的作用以及自噬对NLRP3炎性小体的相互调节作用。我们重点关注线粒体和线粒体自噬在激活和调节NLRP3炎性小体中的作用。最后，我们详细阐述病理性NLRP3反应在肺部疾病发生和表现中的影响。
