ABSTRACT
Atopic asthma is a chronic lung disease of lower airways caused mainly due to action of T-helper (Th) 2 type cytokines, eosinophilic inflammation, mucus hypersecretion and airway remodelling. Interleukin (IL)-33 increases type 2 immunity polarization in airway playing critical role in eosinophilic asthma. On the other hand, NLRP3 inflammasome activation results in the release of caspase-1 (Casp-1) which, in its turn, promotes IL-33 inactivation. Recent studies have shown associations between NLRP3 variants and inflammatory diseases. However, no study with genes in NLRP3 inflammassome route has been conducted so far with asthma and atopy in any population to date. Blood samples were collected from 1246 asthmatic and non-asthmatic children. Associations were tested for single nucleotide polymorphism (SNP)s in NLRP3 and CASP1 with asthma and markers of atopy and in cultures stimulated with Blomia tropicalis (Bt) mite crude extract. The T allele of rs4925648 (NLRP3) was associated with increased asthma risk (OR 1.50, P = 0.005). In addition, the T allele of rs12130711 polymorphism, whithin the same gene, acted as a protector factor for asthma (OR 0.78, P = 0.038). On the other hand, the C allele of rs4378247 NLRP3 variant was associated with lower levels of IL-13 production when peripheral blood cells were stimulated with Bt (OR 0.39, P = 4E-04). In addition, the greater the number of risk alleles in IL33/NLRP3/CASP1 route the greater was the risk for asthma. The T allele of rs7925706 CASP1 variant was also associated with increased risk for asthma (OR 1.47, P = 0.008). In addition, this same allele increased the eosinophil counts in blood (mm3) in asthmatic individuals compared with non-asthmatic (P = 0.0004). These results suggest that NLRP3 and CASP1 polymorphisms may be associated with susceptibility for asthma and markers of atopy in our population.
ABSTRACT
Efficient induction of effector and long-term protective antigen-specific CD8+ T memory response by vaccination is essential to eliminate malignant and pathogen-infected cells. Intracellular infectious bacteria, including Listeria monocytogenes, have been considered potent vectors to carry multiple therapeutic proteins and generate antigen-specific CD8+ T cell responses. Although the role of molecules involved in inflammatory cell death pathways, such as necroptosis (RIPK3-mediated) and pyroptosis (Caspase-1/11-mediated), as effectors of immune response against intracellular bacteria are relatively well understood, their contribution to the adjuvant effect of recombinant bacterial vectors in the context of antigen-specific CD8+ T cell response remained obscure. Therefore, we evaluated the impact of RIPK3 and Caspase-1/11 (Casp-1/11) individual and combined deficiencies on the modulation of antigen-specific CD8+ T cell response during vaccination of mice with ovalbumin-expressing L. monocytogenes (LM-OVA). We observed that Casp-1/11 but not RIPK3 deficiency negatively impacts the capacity of mice to clear LM-OVA. Importantly, both RIPK3 and Casp-1/11 are necessary for optimal LM-OVA-mediated antigen-specific CD8+ T cell response, as measured by in vivo antigen-specific CD8+ T cell proliferation, target cell elimination, and cytokine production. Furthermore, Casp-1/11 and Casp-1/11/RIPK3 combined deficiencies restrict the early initiation of antigen-specific CD8+ T cell memory response. Taken together, our findings demonstrate that RIPK3 and Casp-1/11 influence the quality of CD8+ T cell responses induced by recombinant L. monocytogenes vectors.