Understanding the role of IL-22 in cutaneous leishmaniasis

描述(由申请人提供)：皮肤利什曼病是一种疾病，其特征是溃烂的皮肤损害通常是自我愈合的。然而，一些患者患上了更严重的疾病，无法解决。虽然通过免疫反应控制寄生虫的研究已经很好，但病变如何解决或在某些情况下无法解决的机制还不清楚。有趣的是，有研究表明，促炎免疫反应，而不是不受控制的寄生虫负载，在与不可愈合的损伤相关的病理中起着重要作用。我们已经证明，IL-17在慢性病变的病理过程中扮演着以前未被认识到的角色。这些发现促使我们质疑，在重大利什曼原虫感染期间，还有哪些未知的细胞因子可能在病变病理中发挥作用。IL-22也是由Th17细胞产生的，已被证明通过维持上皮屏障而促进伤口愈合过程。然而，这种细胞因子也与其他促炎性皮肤病的进展有关，如牛皮癣。IL-22的这种病理作用可以受到其他促炎细胞因子的影响。我们假设IL-22在病变的解决中可能具有双重作用。在感染的正常愈合模型中，我们假设IL-22限制了病理并有助于病变的解决。然而，在高度炎症和不可愈合的感染中，IL-22通过促进炎症发挥其病理作用。这项提案的目的将1)调查愈合和非愈合L主要感染期间IL-22的产生动力学以及来源和靶点，2)检查IL-22如何限制愈合感染期间的病理，并确定IL-22是否参与非愈合感染期间的病理。我们希望更好地了解增强IL-22是否可以改善慢性皮肤利什曼病的治疗。然而，建议将IL-22作为一种潜在的治疗方法，需要完全了解这种细胞因子如何在一系列表现中发挥作用。我们认为，解决这项提案中的问题将为我们提供这方面的知识。

DESCRIPTION (provided by applicant): Cutaneous leishmaniasis is a disease characterized by ulcerating skin lesions that are normally self- healing. However some patients develop more severe disease that fails to resolve. While parasite control by the immune response has been well studied, the mechanisms of how lesions resolve, or in some cases fail to resolve, is not well understood. Interestingly, it has been suggested that a pro-inflammatory immune response, rather than an uncontrolled parasite load, plays a large role in the pathology associated with non-healing lesions. We have demonstrated that IL-17 plays a previously unappreciated role in mediating pathology in chronic lesions. These findings prompted us to question what other unknown cytokines could have a role in lesion pathology during Leishmania major (L. major) infections. IL-22, also produced by Th17 cells, has been shown to contribute to the wound healing process through maintenance of the epithelial barrier. However, this cytokine has also been implicated in the progression of other pro-inflammatory skin diseases, like psoriasis. This pathologic role of IL-22 can be influenced by the presence of other pro-inflammatory cytokines. We hypothesize that IL-22 could have dual roles in lesion resolution. In a normal healing model of infection, we hypothesize that IL-22 limits pathology and assists in lesion resolution. However, in a highly inflammatory and non-healing infection, IL-22 exercises its pathologic roles through promoting inflammation. The aims of this proposal will 1) investigate the kinetics of production as well as the sources and targets of IL-22 during healing and non-healing L. major infections and 2) examine how IL-22 limits pathology during healing infections and determine if IL-22 contributes to pathology during non-healing infections. We hope to better understand if augmenting IL-22 could improve treatment of chronic cutaneous leishmaniasis. However, suggesting IL-22 as a potential therapeutic requires the complete understanding of how this cytokine functions in a spectrum of manifestations. We believe that addressing the questions in this proposal will provide us with that knowledge.