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by claude@2026-07, 2026-07-16
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The paper investigates how high temperature (fever-range heat) influences NLRP3 inflammasome activation in macrophages, asking whether NLRP3 is a temperature-sensitive negative-feedback “thermosensor.” Using short-term high-temperature incubations, the authors find that elevated temperature markedly inhibits NLRP3 activation and inflammasome formation, while inflammasome-independent cytokine secretion (TNF and IL-6) is much less affected, and the inhibition is transcription-independent and protein-intrinsic compared with other inflammasomes (NLRC4, AIM2, NLRP1). They report that increased temperature decreases NLRP3 thermal stability, implicates a flexible C-terminal COFI peptide in the FISNA domain via molecular simulations, and shows COFI regulation is required for NLRP3 activation; in mice, high temperature exposure attenuates inflammatory cytokine production after in vivo LPS challenge. This paper is centrally about endometriosis or adenomyosis only tangentially; it does not explicitly discuss endometriosis or adenomyosis, and was included in the corpus via upstream keyword matching.
Abstract
Inflammation is an essential response to infection and injury, but unregulated inflammation is damaging and must be limited by negative feedback signalling. Inflammasome signalling drives local inflammation and systemic responses like fever. However, our understanding of how inflammasome signalling is negatively regulated is limited. NLRP3 is activated by a vast number of stimuli and senses perturbations of cytoplasmic homeostasis. As temperature is a fundamental environmental stressor, we hypothesised that NLRP3 inflammasome signalling would be sensitive to increased temperatures and so we investigated the effects of high temperatures on NLRP3 in macrophages. Short-term incubation at high fever range temperatures significantly inhibits NLRP3 activation, while secretion of the inflammasome-independent cytokines TNF and IL-6 are much less affected. High temperature blocks NLRP3 inflammasome formation in a transcription-independent manner, and NLRP3 is highly sensitive to temperature-mediated inhibition relative to the NLRC4, AIM2, and NLRP1 inflammasomes. Using cellular assays and molecular simulations we show that the effect of high temperature on NLRP3 is protein intrinsic. NLRP3 activation is associated with a decrease in the thermal stability of the protein and multiscale molecular dynamics simulations identified a peptide in the C -terminal o f the FI SNA domain (COFI) that is highly flexible and undergoes a significant conformational shift at high temperature. Cellular assays demonstrate that the COFI regulates NLRP3 stability and is required for activation. Furthermore, mice exposed to high temperature display attenuated inflammatory cytokine production upon in vivo LPS challenge. Our studies thus reveal that high temperatures associated with fever limit NLRP3 activity and identify a novel role for NLRP3 as a protein thermosensor.
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Abstract
Inflammation is an essential response to infection and injury, but unregulated inflammation is damaging and must be limited by negative feedback signalling. Inflammasome signalling drives local inflammation and systemic responses like fever. However, our understanding of how inflammasome signalling is negatively regulated is limited. NLRP3 is activated by a vast number of stimuli and senses perturbations of cytoplasmic homeostasis. As temperature is a fundamental environmental stressor, we hypothesised that NLRP3 inflammasome signalling would be sensitive to increased temperatures and so we investigated the effects of high temperatures on NLRP3 in macrophages. Short-term incubation at high fever range temperatures significantly inhibits NLRP3 activation, while secretion of the inflammasome-independent cytokines TNF and IL-6 are much less affected. High temperature blocks NLRP3 inflammasome formation in a transcription-independent manner, and NLRP3 is highly sensitive to temperature-mediated inhibition relative to the NLRC4, AIM2, and NLRP1 inflammasomes. Using cellular assays and molecular simulations we show that the effect of high temperature on NLRP3 is protein intrinsic. NLRP3 activation is associated with a decrease in the thermal stability of the protein and multiscale molecular dynamics simulations identified a peptide in the C-terminal of the FISNA domain (COFI) that is highly flexible and undergoes a significant conformational shift at high temperature. Cellular assays demonstrate that the COFI regulates NLRP3 stability and is required for activation. Furthermore, mice exposed to high temperature display attenuated inflammatory cytokine production upon in vivo LPS challenge. Our studies thus reveal that high temperatures associated with fever limit NLRP3 activity and identify a novel role for NLRP3 as a protein thermosensor.
Competing Interest Statement
RCC is a co-inventor on patents and patent applications for NLRP3 inhibitors which have been licensed to Inflazome Ltd, Ireland. RCC is a consultant for BioAge Labs, USA (since 2020), and serves on the Scientific Advisory Board of Viva in Vitro Diagnostics, Spain (since 2024). DB is a past employee and shareholder of IFM Therapeutics (unrelated to this work). All other authors have no competing interests.
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