Abstract
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.
Highlights
Ozone (O3) is an environmental pollutant generated by chemical reactions of automobile emissions (NO and hydrocarbons) with sunlight
Factorial ANOVA demonstrated that O3 increased bronchoalveolar lavage (BAL) neutrophils, macrophages, and protein (Fig. 2), consistent with previous reports by ourselves and others using this type of O3 exposure [8,24]
We have previously reported that BAL concentrations of adiponectin increase following subacute O3 exposure and that O3-induced neutrophilic influx into the lungs is augmented in mice deficient in adiponectin [8]
Summary
Ozone (O3) is an environmental pollutant generated by chemical reactions of automobile emissions (NO and hydrocarbons) with sunlight. O3 acts as oxidizing agent on cell membranes and on proteins and lipids in the lung and airway lining fluid, leading to epithelial injury and an inflammatory response that includes induction of acute phase cytokines and chemokines, and neutrophil influx [1,2,3]. Adiponectin, an adipose-derived hormone that decreases in obesity [4], has important anti-inflammatory effects. Exogenous administration of adiponectin decreases allergic airways inflammation in mice [7]. We have previously reported that compared to wildtype (WT) mice, adiponectin deficient (Adipo2/2) mice exposed to subacute O3 (0.3 ppm for 24 to 72 h) have increased neutrophilic inflammation, and increased pulmonary expression of certain cytokines and chemokines, including IL-17A and G-CSF [8]
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