Editorial: NLRP3 activation and regulation in innate immune responses

COPYRIGHT © 2023 Mortellaro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 08 March 2023 DOI 10.3389/fimmu.2023.1171138

The tight regulation of the NLRP3 inflammasome pathway is crucial for maintaining proper immune function and preventing excessive inflammation. The mechanisms of NLRP3 inflammasome activation may depend on the specific context and cell type. While priming is a well-established step for NLRP3 inflammasome activation in many cell types, including murine macrophages, Gritsenko et al. report that priming might be dispensable for NLRP3 inflammasome activation in human monocytes in vitro. When human monocytes are treated with nigericin, it induces K+ and Cl-efflux, which triggers the assembly of the NLRP3 inflammasome complex, leading to IL-1b and IL-18 release. Inflammasome activation is also peculiar in neutrophils in several ways. Inflammasome activation in neutrophils is often associated with NETosis, a specialized form of programmed cell death in which neutrophils release net-like structures called neutrophil extracellular traps (NETs). Münzer et al. show that, under sterile conditions, neutrophils can assemble and activate the NLRP3 inflammasome with the support of the enzyme PAD4 (peptidyl arginine deiminase 4), which is involved in chromatin decondensation and NET formation. In addition, Keitelman et al. reveal that serine proteases support caspase-1 in the processing and secretion of IL-1b in human neutrophils via the autophagic pathway. Son et al. present another key feature of inflammasome activation in neutrophils. When exposed to a milieu enriched in DAMPs, neutrophils are resistant to pyroptosis and mitochondrial depolarization in response to a NLRP3 inflammasome activator. In contrast, macrophages are desensitized via a mechanism leading to mitochondrial depolarization and pyroptosis. Based on these results, they propose that neutrophils are the primary source of IL-1b released in DAMP-rich inflammatory districts.
On this Research Topic, some articles emphasize the contribution of excessive and chronic inflammasome activation in the pathogenesis of various inflammatory diseases. Huot-Marchand et al. demonstrate that the NLRP3 inflammasome and GSDMD are key players in pulmonary inflammation and remodeling upon acute or sub-chronic mouse exposure to cigarette smoke. Li et al. report that a 4-benzene-indol derivative ameliorates LPS-induced sepsisrelated acute lung injury by disrupting NLRP3-NEK7 interaction and the subsequent inflammasome assembly and activation. Wang et al. focus on the role of the inflammasome-induced IL-1 release in the development and progression of spinal cord injury. Inhibition of caspase-4 (involved in NLRP3 inflammasome activation) and IL-1mediated pathway attenuate inflammation and promote repair of the injured spinal cord by inhibiting NF-kB signaling, NLRP3 inflammasome, and GSDMD-mediated pyroptosis. The potential role of inflammasomes and pyroptosis in relation to liver fibrosis is reviewed in Gan et al. They particularly focus on the effect of inflammasome activation in various liver cells (i.e., hepatocytes, cholangiocytes, hepatic stellate cells, hepatic macrophages, and liver sinusoidal endothelial cells) and how the pharmacological treatment of inflammasomes can be exploited as a potential strategy for attenuating liver fibrosis.
To summarize, this Research Topic, with a variety of articles, has provided important new insights into the activation mechanisms of the NLRP3 inflammasome and its link with a number of diseases and conditions.

Author contributions
The author confirms being the sole contributor of this work and has approved it for publication.

Funding
This work was supported by the Else Kröner Fresenius Prize for Medical Research 2020 and a grant from Fondazione Telethon (SR-Tiget Core Grant, Tele21-A5).

Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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