Can NLRP3 (Nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3) activation lead to sexual anhedonia?

From the Guidelines

Yes, NLRP3 activation can lead to sexual anhedonia, as it is associated with the development of depression and anxiety, which are common comorbidities with chronic pain and can lead to sexual dysfunction, including anhedonia 1.

Key Points

• The activation of the NLRP3 inflammasome is linked to the release of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α, which are elevated in patients with depression and anxiety 1.
• Depression and anxiety are highly prevalent in patients with inflammatory diseases, and treatments targeting proinflammatory cytokines have shown an additional effect in reducing depressive symptoms 1.
• The expression of NLRP3 is elevated in patients with depression and anxiety, and polymorphisms of genes encoding inflammatory mediators have been associated with responsiveness to pharmacological treatment of depression and anxiety 1.

Mechanisms

• The recognition of danger-associated molecular patterns (DAMPs) by immunological cells leads to the activation of the inflammatory response, which can result in the development of depression and anxiety 1.
• The activation of the NLRP3 inflammasome is a critical step in the inflammatory response, leading to the release of proinflammatory cytokines and the development of depression and anxiety 1.
• Sexual anhedonia can be a symptom of depression and anxiety, and the activation of the NLRP3 inflammasome may contribute to the development of these conditions, leading to sexual dysfunction, including anhedonia 1.

From the Research

NLRP3 Activation and Sexual Anhedonia

• There is no direct evidence in the provided studies that links NLRP3 activation to sexual anhedonia 2, 3, 4, 5, 6.
• However, study 4 suggests that NLRP3 inflammasome activation is involved in lipopolysaccharide-induced depressive-like behaviors, which may be related to sexual anhedonia.
• The study 4 found that NLRP3 or ASC deficiency attenuated lipopolysaccharide-induced depressive-like symptoms and increased IDO gene expression, which was accompanied by inhibition of lipopolysaccharide-induced microglial activation.
• It is possible that NLRP3 activation may contribute to the development of depressive disorders, which can be associated with sexual anhedonia, but more research is needed to establish a direct link between NLRP3 activation and sexual anhedonia.

Mechanisms of NLRP3 Activation

• The NLRP3 inflammasome is a multiprotein complex that can be activated by pathogens or danger-associated molecular patterns 2.
• The activation of NLRP3 inflammasome involves the assembly of the NLRP3 sensor, adaptor apoptosis-associated speck-like protein (ASC), and effector cysteine protease procaspase-1 3.
• The leucine-rich repeat (LRR) domain of NLRP3 is required for NLRP3 inflammasome activation in macrophages 6.
• Deletion of the LRR domain inhibited NLRP3 self-association, oligomerization, and interaction with the essential regulator NEK7 6.

NLRP3 Activation in Diseases

• NLRP3 inflammasome activation is involved in various diseases, including neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders 3.
• Study 5 found that NLRP3 inflammasome activation is a key pathway in inclusion body myositis, a muscle disease.
• The study 5 also found that altered mitophagy is associated with NLRP3 inflammasome activation in inclusion body myositis.