Inducible costimulator ligand regulates bleomycin-induced lung and skin fibrosis in a mouse model independently of the inducible costimulator/inducible costimulator ligand pathway.

OBJECTIVE: Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin and internal organs, including the lungs. Inducible costimulator (ICOS), which is expressed on activated T cells, and its ligand ICOSL, which is expressed on antigen-presenting cells, have been considered a single receptor-ligand pair. Although the ICOS/ICOSL pathway is known to play various roles in adaptive immunity, its roles in innate immunity and tissue fibrosis remain unknown.
METHODS: We assessed the roles of ICOS and ICOSL in tissue fibrosis by administering bleomycin intratracheally or intradermally into mice deficient in ICOS and/or ICOSL. Tissue fibrosis was evaluated by histologic or biochemical examination.
RESULTS: ICOS deficiency attenuated the lung and skin fibrosis, whereas ICOSL deficiency aggravated it. Mice deficient in both ICOS and ICOSL exhibited accelerated fibrosis, reflecting a dominant role of ICOSL over ICOS in this model. Interestingly, ICOSL expression on macrophages and B cells derived from bronchoalveolar lavage fluid was significantly elevated in ICOS-deficient mice as compared with wild-type mice during this process. Thus, the levels of ICOSL expression on B cells and macrophages were inversely associated with the severity of tissue fibrosis.
CONCLUSION: Our results indicate that ICOSL expression on antigen-presenting cells plays a previously unknown regulatory role during the development of bleomycin-induced tissue fibrosis that is independent of the ICOS/ICOSL pathway. Further studies will be needed to clarify the roles of ICOS and ICOSL in the development of systemic sclerosis.