Caspase-11 Mediates Neutrophil Chemotaxis and Extracellular Trap Formation During Acute Gouty Arthritis Through Alteration of Cofilin Phosphorylation

Gout is characterized by attacks of arthritis with hyperuricemia and monosodium urate (MSU) crystal-induced inflammation within joints. Innate immune responses are the primary drivers for tissue destruction and inflammation in gout. MSU crystals engage the Nlrp3 inflammasome, leading to the activation of caspase-1 and production of IL-1β and IL-18 within gout-affected joints, promoting the influx of neutrophils and monocytes. Here, we show that caspase-11−/− mice and their derived macrophages produce significantly reduced levels of gout-specific cytokines including IL-1β, TNFα, IL-6, and KC, while others like IFNγ and IL-12p70 are not altered. IL-1β induces the expression of caspase-11 in an IL-1 receptor-dependent manner in macrophages contributing to the priming of macrophages during sterile inflammation. The absence of caspase-11 reduced the ability of macrophages and neutrophils to migrate in response to exogenously injected KC in vivo. Notably, in vitro, caspase-11−/− neutrophils displayed random migration in response to a KC gradient when compared to their WT counterparts. This phenotype was associated with altered cofilin phosphorylation. Unlike their wild-type counterparts, caspase-11−/− neutrophils also failed to produce neutrophil extracellular traps (NETs) when treated with MSU. Together, this is the first report demonstrating that caspase-11 promotes neutrophil directional trafficking and function in an acute model of gout. Caspase-11 also governs the production of inflammasome-dependent and -independent cytokines from macrophages. Our results offer new, previously unrecognized functions for caspase-11 in macrophages and neutrophils that may apply to other neutrophil-mediated disease conditions besides gout

Can NLRP3 gene polymorphism in Egyptian chronic hepatitis C patients affect the degree of liver fibrosis?

Background: The cytokines genes polymorphisms are important determinants for the outcome of HCV infection and degree of liver fibrosis and inflammation. Recently, it has been revealed that hepatocytes and hepatic macrophages produce mature IL-1β through the NLRP3 (NOD-like receptor, pyrin domain containing 3) inflammasome assembly which represents a link between hepatitis C virus infection and liver inflammation. In addition, NLRP3 inflammasome has emerged as a cytoplasmic sensor of HCV participating in eliciting the innate immune response against HCV. Objective: To explore the association of a genetic variation within 3’UTR NLRP3 gene with the degree of liver fibrosis and /or liver inflammation. Moreover, to investigate possible relation between fibrosis and the HCV load quantified at the diagnosis of Egyptian HCV patients. Methods: We studied the distribution of genotypes and alleles of one NLRP3 SNP (rs10754558) in one hundredforty seven chronic HCV patients using Taq Man predesigned SNP genotyping assay. Results: The genotype distribution and allele frequencies of NLRP3 (rs10754558) polymorphism did not differ significantly neither with the degree of liver fibrosis nor with the degree of liver inflammation or the baseline HCV quantity. Conclusions: NLRP3 (rs10754558) polymorphism was not associated neither with the degree of liver fibrosis nor with the degree of liver inflammation and amplitude of baseline HCV load measured during diagnosis of Egyptian patients chronically infected with HCV genotype 4a. Importantly, the pivotal role played by the NLRP3 in the immune response against HCV infection requires further studies for other polymorphisms within NLRP3 gene to unravel their role in HCV infection

Inflammasome Genes’ Polymorphisms in Egyptian Chronic Hepatitis C Patients: Influence on Vulnerability to Infection and Response to Treatment

Chronic inflammation is a pivotal contributor to the liver damage mediated by hepatitis C virus (HCV). The NOD-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome is activated by HCV in both hepatocytes and Kupffer cells. The aim of our study was to investigate the association of nine single-nucleotide polymorphisms in four inflammasome genes (NLRP3, CARD8, IL-1β, and IL-18) with the susceptibility to HCV infection and outcome of interferon treatment in 201 Egyptian chronic hepatitis C patients and 95 healthy controls. The genotyping was conducted using TaqMan predesigned SNP assay. In the comparative analysis, the CC genotype of the NLRP3 rs1539019 was found to be associated with the lower risk to chronic HCV infection (OR: 0.33, 95% CI: 0.17-0.62). This association was also found for the CA genotype and the A allele of the NLRP3 rs35829419 (OR: 0.18 and 0.22, respectively), in addition to the GG genotype and G allele of IL-18 rs1946518 (OR: 0.55 and 0.61, respectively). In contrast, the AA genotype of the IL-1β rs1143629 was significantly more frequent in HCV patients (OR: 1.7, 95% CI: 1-2.86). Notably, the frequency of the AA genotype of NLRP3 rs1539019 was significantly higher in patients with lack of response (NR) to the interferon treatment (OR: 1.95, 95% CI: 1-3.7). A similar association was found for both the CC genotype and C allele of the NLRP3 rs35829419 (OR: 2.78 and 2.73, respectively) and for the TT genotype and T allele of CARD8 rs2043211 (OR: 2.64 and 1.54, respectively). Yet, the IL-1β (rs1143629, rs1143634) and IL-18 (rs187238, rs1946518) polymorphisms did not show any significant association with response to interferon treatment. In conclusion, this study reports, for the first time, the association of genetic variations in NLRP3 with hepatitis C susceptibility and response to treatment in Egyptian patients. However, further large-scale studies are recommended to confirm our findings