The NLRP3 inflammasome in depression: A narrative review from neuroinflammation to novel therapeutic approaches

Abstract

This review examines the role of the NLRP3 inflammasome in the pathogenesis of depression, with an emphasis on its inflammatory functions and implications for therapeutic development. Depression is a prevalent and debilitating mental disorder characterized by persistent low mood, yet its underlying mechanisms remain incompletely elucidated. Growing evidence implicates inflammation in the onset and progression of depression, attracting increasing research attention. As a key regulator of innate immunity, the NLRP3 inflammasome appears to contribute significantly to depressive pathology. Current research frequently centers on NLRP3-mediated neuroinflammation and associated therapeutic strategies. Clarifying the structure and activation mechanisms of the NLRP3 inflammasome helps elucidate its role as an upstream regulator of multiple neuroinflammatory pathways. The NLRP3 inflammasome thus functions as a convergent signaling node through which diverse risk factors—such as stress and metabolic dysregulation—trigger neuroinflammation, subsequently affecting neurotransmission and neural plasticity. Targeting NLRP3 may therefore represent a strategic approach for developing new antidepressant therapies by concurrently mitigating multiple downstream inflammatory mediators. Such strategies could yield novel treatments acting on specific molecular pathways. This review underscores the significance of the NLRP3 inflammasome in depression and supports future endeavors to translate mechanistic insights into clinically effective anti-inflammatory interventions. • This review clarifies the NLRP3 inflammasome’s pivotal role in depression pathogenesis as a convergent signal node integrating risk factors triggering neuroinflammation and linking peripheral insults to central pathology. • Clinical and preclinical evidence supports NLRP3-depression association depressed patients show elevated NLRP3-related inflammatory markers in peripheral cells and post-mortem brain tissue preclinical models link NLRP3 activation to depressive-like behaviors ameliorated by NLRP3 knockout or inhibition. • The review outlines multicellular multipathway mechanisms of NLRP3-driven depression promoting microglial M1 polarization and proinflammatory cytokine release enhancing astrocyte inflammation and disrupting blood-brain barrier inducing neuronal pyroptosis and impairing neurotransmitter systems neuroplasticity to mediate depressive phenotypes. • It summarizes promising NLRP3-targeted antidepressant strategies including natural compounds synthetic drugs and non-pharmacological interventions all inhibiting NLRP3 via distinct mechanisms.

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