A Novel TLR4-Binding Domain of Peroxiredoxin From Entamoeba histolytica Triggers NLRP3 Inflammasome Activation in Macrophages

Abstract

Macrophages promote early host responses to infection by releasing pro-inflammatory cytokines, and they are crucial to combat amoebiasis, a disease affecting millions of people worldwide. Macrophages elicit pro-inflammatory responses following direct cell/cell interaction of Entamoeba histolytica, inducing NLRP3 inflammasome activation with high-output IL-1β/IL-18 secretion. Here, we found that trophozoites could upregulate peroxiredoxins (Prx) expression and abundantly secrete Prxs when encountering host cells. The C-terminal of Prx was identified as the key functional domain in promoting NLRP3 inflammasome activation, and a recombinant C-terminal domain could act directly on macrophage. The Prxs derived from E. histolytica triggered toll-like receptor 4-dependent activation of NLRP3 inflammasome in a cell/cell contact-independent manner. Through genetic, immunoblotting or pharmacological inhibition methods, NLRP3 inflammasome activation was induced through caspase-1-dependent canonical pathway. Our data suggest that E. histolytica Prxs had stable and durable cell/cell contact-independent effects on macrophages following abundantly secretion during invasion, and the C-terminal of Prx was responsible for activating NLRP3 inflammasome in macrophages. This new alternative pathway may represent a potential novel therapeutic approach for amoebiasis, a global threat to millions.

Prx4 acts as DAMP in shrimp, enhancing bacterial resistance via the toll pathway and prophenoloxidase activation

“… 32 The C-terminal domain of peroxiredoxin in anaerobic parasitic amoebozoan, Entamoeba histolytica , also triggered TLR4-dependent activation of NLRP3 inflammasome in macrophages through caspase-1-dependent canonical pathway. 50 The mechanism of immune response activation following r Lv Prx4 injection may involve the regulation of antimicrobial peptides and interferons through Toll pathway as the presented data indicate that r Lv Prx4 injection could not promote the expression of LvPEN4 and LvVago5 when LvTLR1 or LvTLR2 was inhibited ( Figure 8 ). Of interest, LvALF AA-K was overexpressed in r Lv Prx4-injected shrimp and was upregulated despite silencing of the toll-like receptor.…”

Loss of NLRP3 reduces oxidative stress and polarizes intratumor macrophages to attenuate immune attack on endometrial cancer

“…Since we found that ROS expression is reduced in NLRP3-depleted macrophages, it may be interesting to examine the changes in MPO in a future study. The Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-kB) pathways play a crucial role in the innate immune response to bacterial LPS (28). This pathway is activated when TLR4 recognizes LPS and triggers NF-kB, which then regulates the expression of proinflammatory cytokines and other genes involved in the immune response, likely through the NLRP3 protein (28).…”

“…The Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-kB) pathways play a crucial role in the innate immune response to bacterial LPS ( 28 ). This pathway is activated when TLR4 recognizes LPS and triggers NF-kB, which then regulates the expression of pro-inflammatory cytokines and other genes involved in the immune response, likely through the NLRP3 protein ( 28 ). In the absence of NLRP3, the activation of the TLR4/NF-kB pathway in macrophages may be diminished or altered, leading to changes in the expression of pro-inflammatory cytokines and other immune response genes ( 28 ).…”

“…This pathway is activated when TLR4 recognizes LPS and triggers NF-kB, which then regulates the expression of pro-inflammatory cytokines and other genes involved in the immune response, likely through the NLRP3 protein ( 28 ). In the absence of NLRP3, the activation of the TLR4/NF-kB pathway in macrophages may be diminished or altered, leading to changes in the expression of pro-inflammatory cytokines and other immune response genes ( 28 ). This could be one of the molecular mechanisms underlying the impact of NLRP3 depletion on macrophages and its effect on cancer biology, as observed in this study.…”

Quantitative Proteomics Reveals Metabolic Reprogramming in Host Cells Induced by Trophozoites and Intermediate Subunit of Gal/GalNAc Lectins from Entamoeba histolytica

“…The adhesion of amoebic trophozoites to colonic epithelial cells mainly depends on the Gal/GalNAc lectins ( 5 , 11 , 26 ). Once amoeba trophozoites adhere to host cells, a series of amoebic reactions are triggered, including the release of amoebapore, cysteine proteases, and peroxiredoxin, as well as trogocytosis, contributing to cell killing and tissue invasion ( 8 , 9 , 15 , 27 , 28 ). Our research lines focus on how host cells respond before apoptosis or phagocytosis induced by E. histolytica trophozoites.…”