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S100 A8/9异二聚体激活免疫细胞和血管内皮， 增加白细胞进入银屑病组织。银屑病中白细胞运输增加导致 单核细胞从血液中浸润，巨噬细胞和髓样树突状细胞分化，以及T 细胞激活在T细胞活化时，髓样单核细胞产生的TNFa由此增加， 介导银屑病皮肤变化。我们假设S100 A8/A9作为一种损伤相关蛋白， 分子模式分子（DAMP）募集、激活和分化单核细胞为银屑病 皮肤我们进一步预测，阻断A8/A9活性或巨噬细胞向未参与的细胞募集， 组织将阻止银屑病表型的发展。 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/或激活是否是致病的， 取决于S100 A8/A9水平。“衬里巨噬细胞”的功能和分化状态 这些特定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，但也来自衬于DEJ的基底角质形成细胞。我们将决定 S100蛋白介导髓样单核细胞（活化的）谱的活化或分化 单核细胞、DC、巨噬细胞），并且如果巨噬细胞对于 银屑病病变使用异种移植模型。我们提出以下具体目标： 确定银屑病皮肤中的髓样单核细胞是否被激活至炎性状态，和/或 分化为巨噬细胞（DEJ衬里或血管）以及S100 A8/A9异二聚体在此过程中的作用。 过程目的II：明确巨噬细胞和S100 A8/A9在银屑病临床反应中的作用， 银屑病的鼠异种移植模型。 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免疫应答的影响。 对角质形成细胞的直接作用表明了一种组合的病理学， 与遗传易感性，导致活动性银屑病。干扰（即，消除）与任何一个细胞 这种三联征的组成部分在疾病中可能（并且已经）导致临床改善。因此，我们认为， 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， 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 治疗牛皮癣的方法