Pathological analysis of skin fibrosis, focused on type 2 innate immune lymphoid cells

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We have studied the mechanism of cryopyrin-associated periodicsyndrome (CAPS), in which an active mutant of NLRP3 spontaneously forms inflammasome andinduces hyper-production of IL-1β. This study led us to focus on the pivotal role of IL-1 in skindiseases. Recently, people pay attention to another IL-1 family molecule, IL-33, because IL-33released from damaged cells in inflammation is critically involved in inflammatory response by aproduction of Th2 cytokines and a degranulation of mast cells. In addition, IL-33 induces a largeamount of Th2 cytokine production from innate lymphoid cells (ILCs). ILCs are newly identifiedlymphoid lineage cells, keep haematopoietic stem cell markers and are present in the mesentericfat-associated lymphoid clusters.Interestingly, the structure of mesenteric fat-associated lymphoid clusters shares thesimilar feature with that of aggregated clusters of lymphoid cells in subcutaneous fat in localizedscleroderma. Also serum IL-33 is reported to be elevated in scleroderma and serum levels of IL-33is well correlated with the severity of cutaneous sclerosis in scleroderma. Therefore, we studied therole of IL-33 in bleomycin-induced scleroderma murine model by comparing the effect in IL-33deficient mice and wild type mice.Six weeks after bleomycin-treatment, we obtained localized cutaneous sclerosisaccompanied with increased skin fibrosis in wild type mice. However, lymphoid cell infiltrationwas not observed in the skin lesion. Unfortunately, the cutaneous sclerosis including histologicalfeatures in IL-33 deficient mice was almost identical to that in wild type mice. We concluded from these results that we should verify the cutaneous role of IL-33 by focusing on Th2 immuneresponse, and now we are establishing such a model to confirm it.