Mechanistic Insight Into the Activation of the NLRP3 Inflammasome by Neisseria gonorrhoeae in Macrophages

Abstract

Gonorrhea is a type III legal communicable disease caused by Neisseria gonorrhoeae (NG), one of the most common sexually transmitted bacteria worldwide. NG infection can cause urethritis or systemic inflammation and may lead to infertility or other complications. The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is a protein complex composed of NLRP3, apoptosis-associated speck-like protein and caspase-1 and is an important part of the cellular machinery controlling the release of interleukin (IL)-1β and IL-18 and the pathogenesis of numerous infectious diseases. It has been reported that NG infection activates the NLRP3 inflammasome; however, the underlying mechanism remain unclear. In this report, the signaling pathways involved in the regulation of NG-mediated NLRP3 inflammasome activation in macrophages were studied. The results indicated that viable NG, but not heat-killed or freeze/thaw-killed NG, activated the NLRP3 inflammasome in macrophages through toll-like receptor 2, but not toll-like receptor 4. NG infection provided the priming signal to the NLRP3 inflammasome that induced the expression of NLRP3 and IL-1β precursor through the nuclear factor kappa B and mitogen-activated protein kinase pathways. In addition, NG infection provided the activation signal to the NLRP3 inflammasome that activated caspase-1 through P 2 X 7 receptor-dependent potassium efflux, lysosomal acidification, mitochondrial dysfunction, and reactive oxygen species production pathways. Furthermore, we demonstrated that NLRP3 knockout increased phagocytosis of bacteria by macrophages and increases the bactericidal activity of macrophages against NG. These findings provide potential molecular targets for the development of anti-inflammatory drugs that could ameliorate NG-mediated inflammation.

Activation of NLRP3 by uropathogenic Escherichia coli is associated with IL-1β release and regulation of antimicrobial properties in human neutrophils

“…Results obtained by Dey et al have previously shown that bone marrow-derived mice macrophages lacking NLRP3 exhibited increased ROS-production and increased ability to limit Trypanosoma cruzi infection compared to wild-type macrophages 55 . NLRP3 knockout macrophages have also been shown to increase phagocytosis of Neisseria gonorrhoeae 56 and deletion of NLRP3 enhanced neutrophil phagocytosis in a polymicrobial sepsis mouse model 57 . The underlying mechanism for the enhanced phagocytosis was found to be associated with increased expression of macrophage receptor with collagenous structure (MARCO) and mannose-binding lectin (MBL) on the surface of NLRP3 knockout neutrophils 57 .…”

Progesterone Suppresses Neisseria gonorrhoeae-Induced Inflammation Through Inhibition of NLRP3 Inflammasome Pathway in THP-1 Cells and Murine Models

“…Previous study demonstrated that gonococcal activated the NLRP3 inflammasome in THP-1 cells ( Duncan et al, 2009 ; Li et al, 2019 ). The IL-1β ( Figure 2D ), IL-18 ( Figure 2E ) levels in the vaginal secretions in intact group were significantly higher than that observed in control group on the 5th day after inoculation.…”

“…Inflammatory stimuli (such as TLRs activation) trigger the initiation of NLRP3 inflammasome by activating NF-κB, thereby inducing IL-1β and NLRP3 mRNA expression ( Dinarello, 2009 ). Although previous studies have shown that lipooligosaccharide (LOS) can induce the pro-inflammatory cytokines through the TLR4-NF-κB pathway ( Packiam et al, 2014 ; Casson et al, 2015 ), a recent study indicated that the first signal of the gonococciinduced-NLRP3 inflammasome activation was not dependent on TLR4, or TLR2 ( Li et al, 2019 ). Strain MS11, an Opa positive strain, was showed to increase the IL-1β secretion in neutrophil ( Sintsova et al, 2014 ).…”

“…P4 can attenuate the release of mitochondrial ROS and blocks the mitochondrial permeability transition pore (mPTP) in mouse models ( García et al, 2016 ). Although there has been evidence showing that N. gonorrhoeae could activate NLRP3 inflammasome ( Li et al, 2019 ), the relationship between inflammasome induced by gonococci and P4 remains unknown.…”

Immunoinformatics Prediction of an Epitope Based Peptide Vaccine for Neisseria Gonorrhea Dihydrolipoamide Acetyltransferase Protein

“…The infection can ascend, causing salpingitis, pelvic inflammatory disease (PID), bacteremia, and it can cross the endothelial barrier even disseminated gonococcal infection (DGI) [6]. The pathogenesis of gonorrhea is regulated by macrophages, dendritic cells, neutrophils, T cells, epithelial cells and cytokines [7].N. gonorrhoeae has multiple virulence factors like lipooligosaccharide (LOS), type IV pili, opacity associated (Opa) proteins, and an outer membrane porin PorB, that among other roles will help the bacteria to survive in the presence of serum.…”