Modulation of Chronic Th2 inflammation by the CCR8 Receptor-Ligand Pathway

总结 特应性等慢性过敏性疾病中屏障界面Th 2炎症的调节因子 皮炎和哮喘的特征不如初始阶段。然而效应器功能 Th 2炎症慢性期白细胞的减少驱动有症状的人类疾病， 与通常无症状过敏原致敏后的许多发病率相关的免疫病理学。 趋化因子是一种趋化性细胞因子，通过结合 靶细胞上的特异性受体。我们最近发现人类趋化因子CCL 18是一种新的 CCR 8受体激动剂。CCL 18是由Th 2细胞因子分化产生的标志性趋化因子 IL-4谱巨噬细胞，M（IL-4）s，也称为交替激活或M2巨噬细胞。 CCL 18与几种慢性和嗜酸性粒细胞炎性人类疾病相关，并且是 在特应性皮炎皮损中诱导最高的趋化因子。M（IL-4）与 最近发现的第2组先天性类嗜酸性细胞（ILC 2）已被证明有助于嗜酸性粒细胞的增殖。 炎症CCR 8也是小鼠ILC 2转录组的顶部标记基因。最近IL-4 R α 阻断，抑制M（IL-4）分化，导致治疗的显着临床改善 难治性特应性皮炎与CCL 18的抑制高度相关。然而， CCL 18和M（IL-4）s维持慢性特应性皮炎的病理学尚不清楚。我们的出版和新的 初步数据使我们假设虽然M（IL-4）在急性炎症中是抗炎的， 它们在屏障界面处经历致病性转化， 炎症，部分通过CCR 8途径和其他介质，以及与细胞的局部相互作用 如ILC 2维持皮肤中的慢性嗜酸性变应性炎症。为了验证这个假设，我们将 使用慢性过敏性皮炎的模型。我们还发现了一种新的小鼠趋化因子激动剂， CCR 8受体是CCL 18的功能类似物。因此，我们建议：（1）确定M（IL-4）是否是 对慢性过敏性炎症至关重要，并确定它们这样做的机制， 受CCR 8通路调节;和（2）定义ILC 2如何促进慢性过敏性炎症， 如果这是由CCR 8通路介导的。我们将确定临床相关的研究建议 在目的1和2中，使用来自湿疹个体的临床样本，将其与健康个体进行比较， 对照

Summary Regulators of Th2 inflammation at the barrier interface in chronic allergic diseases such as atopic dermatitis and asthma are not as well characterized as those in the initiation phase. Yet effector functions of leukocytes in the chronic phase of Th2 inflammation drive symptomatic human disease that results in immune pathology associated with much morbidity after usually asymptomatic allergen sensitization. Chemokines are chemotactic cytokines that control leukocyte recruitment and inflammation by binding specific receptors on target cells. We recently discovered that the human chemokine CCL18 is a novel agonist of the CCR8 receptor. CCL18 is a signature chemokine produced by Th2 cytokine differentiated IL-4 spectrum macrophages, M(IL-4)s, also known as alternatively activated or M2 macrophages. CCL18 is associated with several chronic and eosinophilic inflammatory human diseases, and is one of the most highly induced chemokines in lesional atopic dermatitis skin. M(IL-4) interactions with the recently discovered Group 2 Innate Lymphoid Cells (ILC2) have been shown to facilitate eosinophilic inflammation. CCR8 is also a top signature gene of the mouse ILC2 transcriptome. Recently IL-4Rα blockade, which inhibits M(IL-4) differentiation, resulted in striking clinical improvement of treatment refractory atopic dermatitis that highly correlated with suppression of CCL18. Yet, whether and how CCL18 and M(IL-4)s sustain chronic atopic dermatitis pathology is not known. Our published and new preliminary data lead us to hypothesize that though M(IL-4)s are anti-inflammatory in acute inflammation, they undergo pathogenic transformation at barrier interfaces to become pro-inflammatory in chronic inflammation, and partly through the CCR8 pathway and other mediators, and local interactions with cells such as ILC2s sustain chronic eosinophilic allergic inflammation in the skin. To test this hypothesis we will use a model of chronic allergic dermatitis. We also discovered a novel mouse chemokine agonist of the CCR8 receptor that is a functional analog of CCL18. We thus propose to: (1) Determine if M(IL-4)s are crucial for chronic allergic inflammation and identify mechanisms by which they do so, and if this is regulated by the CCR8 pathway; and (2) Define how ILC2s contribute to chronic allergic inflammation and if this is mediated by the CCR8 pathway. We will determine the clinical correlates of the studies proposed in Aims 1 and 2 using clinical specimens from individuals with eczema that will be compared to healthy controls.