Abstract Introduction Recently, we reported that Card11 (caspase recruitment domain family member 11) substantially contributes to the development of airway hyperresponsiveness (AHR) in high-fat diet (HFD)-induced obese mice by modulating immune responses in both adipose and lung tissues. However, a HFD typically results in excessively overweight mice, which may not be comparable to obese humans. In the present study, we tested the hypothesis that mild obesity, followed by non-specific airway irritation, can induce asthma-like features including AHR in mice. Additionally, we investigated the role of Card11 in this murine model. Methods C57BL/6 mice were fed a HFD for 7 weeks, after which AHR was not observed. These mildly obese mice were then switched to a normal chow diet (NCD) for an additional 3 weeks. During the NCD period, mice received intranasal instillations of either 20 µg of PM10 (particulate matter 10 µm in diameter; PM group) or PBS (PBS group) three times per week. We previously confirmed that this PM10 dose induces minimal immune activation and does not elicit AHR in mice. All measurements, including AHR, were performed at week 11. To evaluate time-specific effects, Card11 signaling was inhibited using Card11 siRNA during either the HFD or NCD period. Results The PM group exhibited significantly enhanced AHR compared with the PBS group. In the PM group, lung and adipose tissue inflammation, collagen deposition, the frequency of type 3 innate lymphoid cells (RORγt⁺ in IL7R⁺ Lin− cells) in lung tissue, and the proportion of classically activated macrophages (CD11c⁺CD206− in CD11b⁺ cells) in adipose tissue were all significantly increased compared with the PBS group. Administration of Card11 siRNA during the HFD period markedly attenuated these changes, including AHR, whereas inhibition of Card11 signaling during the NCD period had no significant effect. Conclusions Mildly obese mice that received intranasal exposure to a low dose of PM10 developed AHR and other asthma-like features. Inhibition of Card11 signaling during the HFD period significantly suppressed AHR, suggesting that Card11 plays a critical role during the weight-gain phase in the pathogenesis of AHR. This murine model may therefore more accurately reflect obesity-associated asthma in humans. This abstract is funded by: None
Park et al. (Fri,) studied this question.