Microglial NLRP3 inflammasome-mediated neuroinflammation and therapeutic strategies in depression

Abstract

Previous studies have demonstrated a bidirectional relationship between inflammation and depression. Activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and NLR family pyrin domain-containing 3 (NLRP3) inflammasomes is closely related to the pathogenesis of various neurological diseases. In patients with major depressive disorder, NLRP3 inflammasome levels are significantly elevated. Understanding the role that NLRP3 inflammasome-mediated neuroinflammation plays in the pathogenesis of depression may be beneficial for future therapeutic strategies. In this review, we aimed to elucidate the mechanisms that lead to the activation of the NLRP3 inflammasome in depression as well as to provide insight into therapeutic strategies that target the NLRP3 inflammasome. Moreover, we outlined various therapeutic strategies that target the NLRP3 inflammasome, including NLRP3 inflammatory pathway inhibitors, natural compounds, and other therapeutic compounds that have been shown to be effective in treating depression. Additionally, we summarized the application of NLRP3 inflammasome inhibitors in clinical trials related to depression. Currently, there is a scarcity of clinical trials dedicated to investigating the applications of NLRP3 inflammasome inhibitors in depression treatment. The modulation of NLRP3 inflammasomes in microglia holds promise for the management of depression. Further investigations are necessary to ascertain the efficacy and safety of these therapeutic approaches as potential novel antidepressant treatments.

Figure 1

Mechanisms underlying NLRP3 inflammasome-mediated neuroinflammation in depression. In the priming process, the GR, P2X7 receptor, TLR4, IL-1R, IL-6R, and TNFR can recognize their corresponding ligands, inducing the NF-κB pathway activation, increased production of NLRP3, pro-IL-18, and pro-IL-1β, and increased expression of IL-6 and TNF-α in microglia. In the protein complex assembly process, GC can bind to GR and then promotes ROS formation. ATP binds to the P2X7 receptor and then induces K⁺ efflux. ROS production, K⁺ efflux, as well as autophagy-lysosomal dysfunction, can promote NLRP3 inflammasome activation. Afterward, caspase-1 is activated by NLRP3 inflammasome, resulting in cytokine and GSDMD cleavage, leading to plasma membrane pore formation that mediates pyroptosis and the release of the mature IL-18 and IL-1β. Created with Microsoft PowerPoint. ASC: Apoptosis-associated speck-like protein containing a caspase recruitment domain; ATP: adenosine triphosphate; DAMPs: danger-associated molecular patterns; GC: glucocorticoid; GR: glucocorticoid receptor; GSDMD: gasdermin D; IL-18: interleukin-18; IL-1R: interleukin-1 receptor; IL-1β: interleukin-1beta; IL-6: interleukin-6; IL-6R: interleukin-6 receptor; NEK7: NIMA-related kinase 7; NF-κB: nuclear factor-kappa B; N-GSDMD: N-terminus of GSDMD; NLRP3: nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3; P2X7: purinergic receptor P2X7; ROS: reactive oxygen species; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor-alpha; TNFR: tumor necrosis factor receptor.

Figure 2

The structures of inhibitors that target the NLRP3 inflammasome pathway for the treatment of depression. The structures were obtained from https://pubchem.ncbi.nlm.nih.gov/ (Kim et al., 2023). (A) BAY 117082; (B) beta-hydroxybutyrate; (C) A438079; (D) MCC950; (E) Cli-095; (F) CY-09; (G) Brilliant Blue G; (H) VX765.