Mice Expressing Cosegregating Single Nucleotide Polymorphisms (D298G and N397I) in TLR4 Have Enhanced Responses to...

Asthma is a common and ubiquitous chronic respiratory disease that is associated with airway inflammation and hyperreactivity resulting in airway obstruction. It is now accepted that asthma is controlled by a combination of host genetics and environment in a rather complex fashion; however, the link between sensing of the environment and development and exacerbation of allergic lung inflammation is unclear. Human populations expressing cosegregating D299G and T399I polymorphisms in the TLR4 gene are associated with a decreased risk for asthma in adults along with hyporesponsiveness to inhaled LPS, the TLR4 ligand. However, these data do not account for other human genetic or environmental factors. Using a novel mouse strain that expresses homologous human TLR4 polymorphisms (TLR4-single nucleotide polymorphism [SNP]), we directly tested the effect of these TLR4 polymorphisms on in vivo responses to allergens using two models of induction. We report that intact TLR4 is required for allergic inflammation when using the OVA and LPS model of induction, as cellular and pathological benchmarks were diminished in both TLR4-SNP and TLR4-deficent mice. However, in the more clinically relevant model using house dust mite extract for induction, responses were enhanced in the TLR4-SNP mice, as evidenced by greater levels of eosinophilic inflammation, Th2 cytokine production, and house dust mite-specific IgG1 production compared with wild-type mice; however, mucus production and airway hyperreactivity were not affected. These results suggest that the TLR4 polymorphic variants (genes) interact differently with the allergic stimulation (environment).