Nuclear receptors modulate inflammasomes in the pathophysiology and treatment of major depressive disorder

Abstract

Major depressive disorder (MDD) is highly prevalent and is a significant cause of mortality and morbidity worldwide. Currently, conventional pharmacological treatments for MDD produce temporary remission in < 50% of patients; therefore, there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms. Accumulated evidence has shown that immune inflammation, particularly inflammasome activity, plays an important role in the pathophysiology of MDD. In this review, we summarize the evidence on nuclear receptors (NRs), such as glucocorticoid receptor, mineralocorticoid receptor, estrogen receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor, in modulating the inflammasome activity and depression-associated behaviors. This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD, and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder.

Keywords: Major depressive disorder; Immune inflammation; Inflammasome; Nuclear receptors

Core Tip: We summarize the evidence on nuclear receptors (NRs), such as glucocorticoid receptor, mineralocorticoid receptor, estrogen receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor, in modulating inflammasome activity and depression-associated behaviors. This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology and treatment of major depressive disorder. Hopefully, the modulation of NRs with hormones and metabolites may become one of the key endocrinologic mechanisms for the development of novel therapeutics to increase the likelihood of therapeutic efficacy.