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

我们研究了低温比林相关周期性综合征(CAPS)的机制，即NLRP3的活性突变体自发形成炎症体，并诱导IL-1β的过度产生。这项研究使我们关注IL-1在皮肤病中的关键作用。最近，另一个IL-1家族分子IL-33受到人们的关注，因为IL-33从炎症中受损的细胞中释放出来，通过产生Th2细胞因子和肥大细胞脱颗粒，在炎症反应中起关键作用。此外，IL-33还能诱导先天淋巴样细胞(ILCs)产生大量Th2细胞因子。ILC是一种新发现的淋巴系细胞，具有造血干细胞标志，存在于肠系膜脂肪相关淋巴集束中。有趣的是，肠系膜脂肪相关淋巴集束的结构与局限性硬皮病皮下脂肪中淋巴样细胞聚集集聚的特征相似。此外，血清IL-33在硬皮病中也有升高的报道，血清IL-33水平与硬皮病皮肤硬化的严重程度有很好的相关性。因此，我们通过比较IL-33缺陷小鼠和野生型小鼠的作用，研究了IL-33在博莱霉素诱导的小鼠硬皮病模型中的作用。在博莱霉素治疗6周后，我们在野生型小鼠皮肤纤维化增加的情况下获得了局限性皮肤硬化。但皮损内未见淋巴样细胞浸润。不幸的是，IL-33缺陷小鼠的皮肤硬化包括组织学特征与野生型小鼠几乎相同。从这些结果我们得出结论，我们应该通过Th2免疫应答来验证IL-33的皮肤作用，现在我们正在建立这样的模型来证实这一点。

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.