Psychosocial stress amplifies inflammation through NLRP3 Inflammasome activated by endoplasmic reticulum stress in the mouse heart

Daphne Diloretto; Gaurav Sarode; Phung N Thai; Jeong Han Lee; Evelyn Navar; Jeong Eun Park; Chaitali Khadilkar; Ning Zong; Yu Jia Dong; Avni Duda; Erick Romero; Pablo E Acevedo; Xiao-Dong Zhang; David A Liem; Imo Ebong; Javier E Lopez; Heejung Bang; Chao-Yin Chen; Leighton Izu; Martin Cadeiras; Ebenezer N Yamoah; Nipavan Chiamvimonvat; Padmini Sirish

doi:10.1016/j.yjmcc.2025.07.008

Psychosocial stress amplifies inflammation through NLRP3 Inflammasome activated by endoplasmic reticulum stress in the mouse heart

J Mol Cell Cardiol. 2025 Jul 11:S0022-2828(25)00119-1. doi: 10.1016/j.yjmcc.2025.07.008. Online ahead of print.

Authors

Daphne Diloretto¹, Gaurav Sarode², Phung N Thai¹, Jeong Han Lee³, Evelyn Navar², Jeong Eun Park², Chaitali Khadilkar², Ning Zong², Yu Jia Dong², Avni Duda², Erick Romero⁴, Pablo E Acevedo⁵, Xiao-Dong Zhang¹, David A Liem⁵, Imo Ebong⁵, Javier E Lopez⁵, Heejung Bang⁶, Chao-Yin Chen⁷, Leighton Izu⁸, Martin Cadeiras⁵, Ebenezer N Yamoah⁹, Nipavan Chiamvimonvat¹⁰, Padmini Sirish¹¹

Affiliations

¹ Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, CA, USA; AHA Strategically Focused Research Network to study Chronic Psychosocial Stressors, Sacramento, CA, USA.
² Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, CA, USA.
³ Department of Translational Neuroscience, University of Arizona, Phoenix, AZ, USA.
⁴ AHA Strategically Focused Research Network to study Chronic Psychosocial Stressors, Sacramento, CA, USA; University of California, Davis HeartShare Clinical Center: Next Generation Phenomics to Define HFpEF, Sacramento, CA, USA.
⁵ Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, CA, USA; AHA Strategically Focused Research Network to study Chronic Psychosocial Stressors, Sacramento, CA, USA; University of California, Davis HeartShare Clinical Center: Next Generation Phenomics to Define HFpEF, Sacramento, CA, USA.
⁶ AHA Strategically Focused Research Network to study Chronic Psychosocial Stressors, Sacramento, CA, USA; University of California, Davis HeartShare Clinical Center: Next Generation Phenomics to Define HFpEF, Sacramento, CA, USA; Department of Public Health Sciences, Division of Biostatistics, University of California, Davis, CA, USA.
⁷ AHA Strategically Focused Research Network to study Chronic Psychosocial Stressors, Sacramento, CA, USA; Department of Pharmacology, University of California, Davis, CA, USA.
⁸ AHA Strategically Focused Research Network to study Chronic Psychosocial Stressors, Sacramento, CA, USA; University of California, Davis HeartShare Clinical Center: Next Generation Phenomics to Define HFpEF, Sacramento, CA, USA; Department of Pharmacology, University of California, Davis, CA, USA.
⁹ AHA Strategically Focused Research Network to study Chronic Psychosocial Stressors, Sacramento, CA, USA; Department of Translational Neuroscience, University of Arizona, Phoenix, AZ, USA.
¹⁰ Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, CA, USA; AHA Strategically Focused Research Network to study Chronic Psychosocial Stressors, Sacramento, CA, USA; University of California, Davis HeartShare Clinical Center: Next Generation Phenomics to Define HFpEF, Sacramento, CA, USA; Department of Basic Medical Sciences, University of Arizona, Phoenix, AZ, USA.
¹¹ Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, CA, USA; AHA Strategically Focused Research Network to study Chronic Psychosocial Stressors, Sacramento, CA, USA; University of California, Davis HeartShare Clinical Center: Next Generation Phenomics to Define HFpEF, Sacramento, CA, USA. Electronic address: psirish@ucdavis.edu.

PMID: 40653306
DOI: 10.1016/j.yjmcc.2025.07.008

Abstract

Psychosocial stress (PSS) affects all humans with different intensities and is known to significantly increase inflammation and cardiovascular disease [1,2]. An amplifier of inflammation is an intracellular multiprotein complex, the inflammasome, activation of which leads to pro-inflammatory cytokines production. However, the mechanisms leading to the inflammasome activation in the heart by PSS are not well understood. Here, we identify critical upstream mechanisms leading to NLRP3 inflammasome activation via endoplasmic reticulum (ER) stress and JAK/STAT pathway. These findings reveal important mechanistic insights into possible upstream targets in controlling excessive inflammation due to PSS.

Keywords: ER stress; Inflammasome; Inflammation; Oxylipins.