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

Abstract

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.

Inducible Costimulator (ICOS) and ICOS Ligand Signaling Has Pivotal Roles in Skin Wound Healing via Cytokine Production

“…Several recent studies, including our bleomycin model, showed the roles of ICOS and ICOSL in innate immune responses, including inflammation. 22,23 Our findings also suggest that ICOS-ICOSL signaling contributes to innate immunity during wound healing. Alternatively, ICOS-ICOSL signaling may affect cytokine balance or the production of cytokines in organs such as the skin under homeostatic and pathological conditions.…”

“…In fact, recent studies suggest involvement of ICOS and ICOSL in innate immune disease models. 22,23 As skin wound healing involves a strong innate immune component, we applied this model to mice deficient for ICOS and ICOSL to investigate the roles of these molecules in modulating innate immunity.…”

The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma

“…Bleomycin (Nippon Kayaku) was dissolved in PBS at a concentration of 1 mg/ml and sterilized by filtration as described previously (33,34). Bleomycin (100 ml) was injected intradermally into the shaved back of the 8 wk-old male BALB/cAJcl mice daily for 4 wk.…”

Impaired IL-17 Signaling Pathway Contributes to the Increased Collagen Expression in Scleroderma Fibroblasts

“…Bleomycin (300 mg) or PBS was injected intradermally into the shaved back of 6-wk-old C57BL/6 mice daily for 4 wk, as described previously (39,40). The back skin was removed on the next day after the final injection, fixed in 10% formalin solution, and embedded in paraffin.…”