Role of the Adiponectin Binding Protein, T-Cadherin (cdh13), in Pulmonary Responses to Subacute Ozone

Adiponectin, an adipose derived hormone with pleiotropic functions, binds to several proteins, including T-cadherin. We have previously reported that adiponectin deficient (Adipo(−/−)) mice have increased IL-17A-dependent neutrophil accumulation in their lungs after subacute exposure to ozone (0.3 ppm for 72 hrs). The purpose of this study was to determine whether this anti-inflammatory effect of adiponectin required adiponectin binding to T-cadherin. Wildtype, Adipo(−/−), T-cadherin deficient (T-cad(−/−)), and bideficient (Adipo(−/−)/T-cad(−/−)) mice were exposed to subacute ozone or air. Compared to wildtype mice, ozone-induced increases in pulmonary IL-17A mRNA expression were augmented in T-cad(−/−) and Adipo(−/−) mice. Compared to T-cad(−/−) mice, there was no further increase in IL-17A in Adipo(−/−)/T-cad(−/−) mice, indicating that adiponectin binding to T-cadherin is required for suppression of ozone-induced IL-17A expression. Similar results were obtained for pulmonary mRNA expression of saa3, an acute phase protein capable of inducing IL-17A expression. Comparison of lung histological sections across genotypes also indicated that adiponectin attenuation of ozone-induced inflammatory lesions at bronchiolar branch points required T-cadherin. BAL neutrophils and G-CSF were augmented in T-cad(−/−) mice and further augmented in Adipo(−/−)/T-cad(−/−) mice. Taken together with previous observations indicating that augmentation of these moieties in ozone exposed Adipo(−/−) mice is partially IL-17A dependent, the results indicate that effects of T-cadherin deficiency on BAL neutrophils and G-CSF are likely secondary to changes in IL-17A, but that adiponectin also acts via T-cadherin independent pathways. Our results indicate that T-cadherin is required for the ability of adiponectin to suppress some but not all aspects of ozone-induced pulmonary inflammation.