Abstract
Previous studies have suggested that activation of the IL-33/ST2 axis as well as elevated expression of the full-length IL-33 precursor acting in an ST2-independent fashion both contribute to pulmonary fibrosis. The protective effect of genetic ST2 deficiency on pulmonary fibrosis is known to be partial, with unclear mechanisms preventing a more complete protection. Here, we report that ST2 deficiency failed to fully protect the lungs from excess collagen accumulation after the profibrotic bleomycin injury and simultaneously facilitated elevations in pulmonary levels of a previously suggested profibrotic mediator, IL-9, as well as a known activator of IL-9 expression, TSLP. Pulmonary CD4+ T cells were the main producers of IL-9. Neutralizing antibody-mediated in vivo blockade of TSLP potently attenuated pulmonary levels of both IL-9 and collagen in the bleomycin injury model in wild-type and particularly ST2-deficient mice. All these observations were markedly pronounced in mice with single deficiency of ST2 and the overall pattern of findings was also preserved in mice with dual deficiency of ST2 and IL-33. It was concluded that the antifibrotic effect of ST2 deficiency is hindered by the simultaneous activation of the TSLP–IL-9 axis in experimental bleomycin-induced pulmonary fibrosis. These findings inform further development of antifibrotic therapies.