The NLRP3 inflammasome: molecular activation and regulation in spermatogenesis and male infertility; a systematic review

Abstract

Background Infertility related to varicocele, infections, metabolic dysfunctions, oxidative stress and environmental toxicants is also associated with inflammatory processes that ultimately lead to the activation of the inflammasome pathway (IP). IP is classically activated by DAMPs, MAMPs or LAMPs, which stand for Damage-, Microbe- or Lifestyle-Associated Molecular Patterns, respectively. The most important player in IP activation is the NLRP3 (NOD[Nuclear oligomerization domain]-, LRR[Leucine rich repeat]- and pyrin domain-containing protein 3) which functions as an intracellular sensor of D/M/L-AMPs resulting in activation of caspase-1, promotion of apoptosis, pyroptosis and generation of inflammatory cytokines. This review addresses the question of whether IP activation might be associated with male infertility situations. Results & conclusions We conducted a systematic review of articles published in the Google Scholar, and PubMed databases through October 2021. It turns out that inflammasome activation and its consequences including cytokine storms, apoptosis and pyroptosis could be associated with the reduced sperm count as well as the structural and functional sperm defects recorded in several situations associated with male infertility suggesting that anti-inflammatory therapeutic strategies could be possibly considered to restore male fertility in future research.

Investigating the Relationship between Tumor Necrosis Factor Alpha-308 and Interleukin-1beta C+3953T Polymorphisms with Male Fertility in Erbil Province

“…The results showed that the genotype CT and allele C were significantly more in unbelieving men and played a role in male infertility, which is consistent with the results of the present study. In other studies, the CT and CC genotypes, which are in line with the results of the present study, were identified as one of the important factors of infertility in men [18][19][20] .…”

Pyrroloquinoline quinone inhibits PCSK9-NLRP3 mediated pyroptosis of Leydig cells in obese mice

“…Conformably, supported by Fan W's efforts and our transcriptome analyses, we have detected that increased pro-inflammatory cytokine NLRP3 accompanying the inhibited T synthesis [71], which was alleviated in PQQ-treated obese mice. Owing to the pyroptosis mediated by NLRP3/Caspase-1/GSDMD is also an essential pathway to the pathogenesis of inflammatory-related male infertility such as male genital tract diseases and abnormal spermatogenesis [72,73], we speculate whether the improvement of PQQ promote T synthesis came into play in management of the LCs pyroptosis induced by obesity. Applying MCC950 (a direct inhibition of NLRP3), we provide in vitro evidence documented that PQQ supplementation exerts suppression of the LCs pyroptosis, recovering the T synthesis with sufficient intracellular cholesterol levels in PA-cultured TM3 cells.…”

Zinc alleviates high fat diet-induced spermatogenic dysfunction in Wistar rats: role of oxidative stress, HMGB1 and inflammasomeEl zinc alivia la disfunción espermatogénica inducida por una dieta rica en grasas en ratas Wistar: papel del estrés oxidativo, HMGB1 y el inflamasoma

“…It has been reported that the inflammasome nucleotidebinding oligomerization domain (NOD)-like receptor family pyrin domain containing-3 (NLRP3) could be associated with obesity and implicated in obesity-induced inflammation [4]. Activation of the inflammasome by damage or microbial or life style associated molecular patterns (DAMP, MAMP, LAMPs) or oxidative stress leads to caspase 1 activation, apoptosis, pyroptosis and release of inflammatory mediators [6,7]. These were suggested to be associated with impairment of spermatogenesis [7,8].…”