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以溃疡性皮肤损伤为特征的疾病，通常是自愈的.然而，一些患者发展出更严重的疾病，无法解决。虽然寄生虫控制的免疫反应已经得到了很好的研究，病变如何解决，或在某些情况下无法解决的机制，是不是很清楚。有趣的是，已经表明促炎性免疫应答，而不是不受控制的寄生虫负荷，在与非愈合性病变相关的病理学中起很大作用。我们已经证明IL-17在慢性病变中介导病理学中起着以前未被认识到的作用。这些发现促使我们质疑其他未知的细胞因子可能在利什曼原虫（L。严重）感染。也由Th 17细胞产生的IL-22已显示通过维持上皮屏障而有助于伤口愈合过程。然而，这种细胞因子也与其他促炎性皮肤病（如银屑病）的进展有关。IL-22的这种病理作用可以受到其他促炎细胞因子的存在的影响。我们假设IL-22在病变消退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限制了病理学并有助于病变消退。然而，在高度炎症和不愈合的感染中，IL-22通过促进炎症发挥其病理作用。本研究的目的是：1）研究IL-22在愈合期和非愈合期的产生动力学以及IL-22的来源和靶点。主要感染和2）检查IL-22如何在愈合感染期间限制病理学，并确定IL-22是否有助于非愈合感染期间的病理学。我们希望更好地了解增加IL-22是否可以改善慢性皮肤利什曼病的治疗。 然而，建议IL-22作为一种潜在的治疗需要完全理解这种细胞因子如何在一系列表现中发挥作用。我们认为，解决本提案中的问题将使我们了解这一点。

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.