S100 A8/A9 and Macrophages in Psoriasis

促炎症的S100A8/9异二聚体激活免疫细胞和血管内皮细胞，导致 导致白血球进入牛皮癣组织的增加。银屑病患者白细胞转运增加导致 单核细胞从血液、巨噬细胞和髓系树突状细胞分化而来，并增加T细胞 细胞激活。当T细胞被激活时，髓系单核细胞产生的TNFcc因此增加 调节牛皮癣的皮肤变化。我们假设S100A8/A9作为相关的损害 分子模式分子(DAMP)招募、激活和分化单核细胞为银屑病患者 皮肤。我们进一步预测，阻断A8/A9活性或巨噬细胞募集到无关者 组织会阻碍牛皮癣表型的发展。 鉴于银屑病组织中衬里巨噬细胞的独特存在，本提案试图解决 巨噬细胞在银屑病皮肤中的积聚和/或激活是否是致病的，如果是 取决于S100A8/A9水平。内衬巨噬细胞的功能及其分化状态 这些特殊的巨噬细胞特别令人感兴趣，因为这些细胞不仅与T细胞并列 来自内皮小静脉，但也到达排列在DEJ的基底角质形成细胞。我们将确定是否 S100蛋白介导髓系单核细胞(激活)谱的激活或分化 单核细胞、树突状细胞、巨噬细胞)，如果巨噬细胞是发展所必需的。 使用异种移植模型的银屑病皮损。我们提出以下具体目标：目标一： 确定银屑病皮肤中的髓系单核细胞是否被激活到炎症状态和/或 分化为巨噬细胞(DEJ衬里或血管)及S100A8/A9异源二聚体在其中的作用 进程。目的II：明确巨噬细胞和S100A8/A9在银屑病临床反应中的作用 银屑病小鼠异种移植模型的建立。 T细胞细胞因子与单核/巨噬细胞细胞因子和趋化因子的相互作用及表型 对角质形成细胞的直接作用表明是一种综合的病理，最终导致信号，共同 具有遗传易感性，会导致活动性牛皮癣。对任何一个蜂窝的干扰(即消除) 这三种疾病的组成部分很可能会导致临床的改善。因此， 了解这些细胞类型之间的关系以及每个组件的重要性 潜在的作用机制(S)，对于增加我们开发治疗方法的可能性至关重要 解决了牛皮癣的全部问题。

The pro-inflammatory S100A8/9 heterodimer activates immune cells and vascular endothelium, leading to increased leukocyte traffic into psoriatic tissue. Increased leukocyte trafficking in psoriasis results in monocyte infiltration from the blood, macrophage and myeloid dendritic cell differentiation, and increased T cell activation. Upon T cell activation, TNFcc produced by myeloid monocytic cells is increased thereby mediating psoriasis skin changes. We hypothesize that S100A8/A9 acting as a damage associated molecular pattern molecule (DAMP) recruits, activates and differentiates monocytes into psoriatic skin. We further predict that blocking A8/A9 activity or macrophage recruitment to the uninvolved tissue will block the development of the psoriasis phenotype. Given the unique presence of lining macrophages in psoriatic tissue, this proposal seeks to address whether the accumulation and/or activation of macrophages in psoriatic skin is pathogenic and if this is dependent upon S100A8/A9 levels. The function of "lining macrophages" and the state of differentiation of these particular macrophages is of particular interest, as these cells are in juxtaposition not only to T cells arriving from endothelial venules, but also to basal keratinocytes lining the DEJ. We will determine whether S100 proteins mediate activation or differentiation of the spectrum of myeloid monocytic cells (activated monocytes, DC, macrophages) in lesional skin, and if macrophages are necessary for the development of psoriatic lesions using a xenogenic transplant model. We propose the following specific aims: Aim I: To determine whether myeloid monocytic cells in psoriasis skin are activated to an inflammatory state and/or differentiated to macrophages (DEJ lining or vascular) and the role of S100A8/A9 heterodimer in this process. Aim II: Todefine the role of macrophages and S100A8/A9 in a clinicalpsoriasis response, and in a murine xenogenic transplant model of psoriasis. The interplay of T cell cytokines with monocyte/macrophage cytokines and chemokines and the apparent direct effect on keratinocytes suggests a combined pathology that ultimately results in signals that, together with genetic susceptibility, lead to active psoriasis. Interference (i.e., elimination) with any one cellular component of this triad in disease is (and has been) likely to lead to clinical improvement. Therefore, understanding the relationship between these cell types as well as the importance of each component and potential mechanism(s) of action, are critical to increasing our likelihood of developing therapeutic modalities that address the totality of psoriasis.