NLRP3/GSDMD mediated pyroptosis induces lung inflammation susceptibility in diesel exhaust exposed mouse strains

Background Genetic diversity among species influences the disease severity outcomes linked to air pollution. However, the pathway responsible for this variability remain elusive and needs further investigation. Objective To investigate the genetic factors and pathways linked with differential susceptibility in mouse strains associated with diesel exhaust exposure. Methods C57BL/6 and Balb/c mice were exposed to diesel exhaust (DE) for 5 days/week for 30 min/day for 8 weeks. Body weight of mice was recorded every week and airway hyperresponsiveness towards DE exposure was recorded after 24 hours of last exposure. Mice were euthanised to collect BALF, blood, lung tissues for immunobiochemical assays, structural integrity and genetic studies. Results C57BL/6 mice showed significantly decreased body weight in comparison to Balb/c mice (p < 0.05). Both mouse strains showed lung resistance and damage to elastance upon DE exposure compared to respective controls (p < 0.05) with more pronounced effects in C57BL/6 mice. Lung histology showed increase in bronchiolar infiltration and damage to the wall in C57BL/6 mice (p < 0.05). DE exposure upregulated pro-inflammatory and Th2 cytokine levels in C57BL/6 in comparison to Balb/c mice. C57BL/6 mice showed increase in Caspase-1 and ASC expression confirming activation of downstream pathway. This showed significant activation of inflammasome pathway in C57BL/6 mice with ∼2-fold increase in NLRP3 and elevated IL-1b expression. Gasdermin-D (GSDMD) levels were increased in C57BL/6 mice demonstrating induction of pyroptosis that corroborated with IL-1b secretion (p < 0.05). Genetic variability among both species was confirmed with sanger’s sequencing suggesting presence of SNPs in 3’UTRs of IL-1b gene influencing expression between mouse strains. Conclusions C57BL/6 mice exhibited increased susceptibility to diesel exhaust in contrast to Balb/c mice via activation of NLRP3-related pyroptosis. Differential susceptibility between strains may be attributed via SNPs in the 3'UTRs of the IL-1β gene.