S100 A8/A9 and Macrophages in Psoriasis

银屑病中的 S100 A8/A9 和巨噬细胞

• 批准号: 8319618
• 负责人: Kevin D Cooper
• 金额: $ 21.58万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319618
• 关键词: Address; Blood; Blood Vessels; Cell Differentiation process; Cells; Clinical; Dendritic Cells; Development; Disease; Genetic Predisposition to Disease; Immune; Infiltration; Inflammatory; Lead; Lesion; Leukocyte Trafficking; Macrophage Activation; Mediating; Modality; Modeling; Molecular; Mus; Myelogenous; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Pathology; Pattern; Phenotype; Process; Psoriasis; Recruitment Activity; Role; S100 Proteins; S100A8 gene; Signal Transduction; Skin; T-Cell Activation; T-Lymphocyte; Therapeutic; Tissues; Translational Research; Transplantation; Triad Acrylic Resin; Vascular Endothelium; cell type; chemokine; cytokine; interest; keratinocyte; macrophage; monocyte; response; venule

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.

促炎性 S100A8/9 异二聚体可激活免疫细胞和血管内皮，从而导致 增加进入银屑病组织的白细胞流量。银屑病中白细胞贩运增加导致 血液中单核细胞浸润，巨噬细胞和髓系树突状细胞分化，T 增加 细胞激活。 T 细胞激活后，髓系单核细胞产生的 TNFcc 增加，从而增加 调节牛皮癣皮肤变化。我们假设 S100A8/A9 充当相关损坏 分子模式分子 (DAMP) 募集、激活单核细胞并将其分化为银屑病 皮肤。我们进一步预测，阻断 A8/A9 活性或巨噬细胞向未涉及的细胞募集 组织将阻止牛皮癣表型的发展。 鉴于银屑病组织中衬里巨噬细胞的独特存在，该提案旨在解决 银屑病皮肤中巨噬细胞的积累和/或激活是否具有致病性，如果是 取决于 S100A8/A9 水平。 “内衬巨噬细胞”的功能和分化状态 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 细胞并置 来自内皮微静脉，但也到达 DEJ 内衬的基底角质形成细胞。我们将确定是否 S100 蛋白介导骨髓单核细胞谱系的激活或分化（激活 病变皮肤中的单核细胞、DC、巨噬细胞），以及巨噬细胞是否是发展所必需的 使用异种移植模型治疗银屑病病变。我们提出以下具体目标： 目标一： 确定牛皮癣皮肤中的骨髓单核细胞是否被激活至炎症状态和/或 分化为巨噬细胞（DEJ 内层或血管）以及 S100A8/A9 异二聚体在此过程中的作用 过程。目标 II：确定巨噬细胞和 S100A8/A9 在银屑病临床反应和治疗中的作用 牛皮癣的小鼠异种移植模型。 T 细胞细胞因子与单核细胞/巨噬细胞细胞因子和趋化因子的相互作用以及表观 对角质形成细胞的直接影响表明了一种综合病理学，最终导致信号一起 具有遗传易感性，导致活动性牛皮癣。对任何一种细胞的干扰（即消除） 疾病中这个三联体的组成部分很可能（并且已经）导致临床改善。所以， 了解这些细胞类型之间的关系以及每个组成部分的重要性和 潜在的作用机制对于增加我们开发治疗方式的可能性至关重要 解决牛皮癣的整体问题。