The receptor NLRP3 is a transcriptional regulator of TH2 differentiation

Abstract

The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1β (IL-1β) and IL-18. Whether NLRP3 can shape immunological function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4(+) T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation.

Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma

“…Both NF-κB activation and Mt-ROS generation have been implicated in the activation of NLRP3 inflammasomes (16,35,47,65,74,75), with emerging data suggesting a role for inflammasomes in a variety of lung diseases (16,31,(44)(45)(46)(76)(77)(78). In a model of house dust mite-induced asthma, airway epithelial NLRP3 expression correlates with enhanced asthma phenotypes, which can be reduced by scavenging Mt-ROS (16).…”

“…Emerging evidence suggests that inflammasomes play a key role in the inflammatory response in asthma (44) by regulating Th2 differentiation and expression of interleukins (35,45,46). In addition, Mt-ROS production has been linked to NLRP3 inflammasome expression and activity (16,35,(47)(48)(49)(50).…”

Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease

“…NLRP3 may also have noncanonical inflammasome-independent roles, such as the transcriptional regulation of T cell differentiation (54). In the hyperoxia-induced ALI model, NLRP3 promotes apoptosis of alveolar epithelial cells by signal transducer and activator of transcription 3 signaling activation (73).…”

Cellular Innate Immunity: An Old Game with New Players

“…Recent studies further highlight that reprogramming or perturbation of distinct metabolic pathways can trigger inflammasome activation, representing an emerging research area in the field of immunometabolism [133][134][135][136][137][138] . Interestingly, while located in the cytoplasm of myeloid cells, NLRP3 can localize in the nucleus of Th2 cells, where it has been shown to act as a transcription factor essential for Th2 polarization and, in a complex with IRF4, to promote IL-4 production, relevant for asthma and melanoma [139] .…”