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

摘要 特应性等慢性变态反应性疾病中屏障界面Th2炎症调节因子的研究 皮炎和哮喘的特征不如初始阶段的好。但效应器功能 处于Th2炎症慢性期的白细胞驱动有症状的人类疾病，导致 免疫病理与通常无症状的过敏原致敏后的发病率有关。 趋化因子是趋化性细胞因子，通过结合控制白细胞的募集和炎症 靶细胞上的特定受体。我们最近发现，人类趋化因子CCL18是一种新的 CCR8受体激动剂。CCL18是由Th2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，又称交替活化或M2级巨噬细胞。 CCL18与几种慢性和嗜酸性炎症性人类疾病有关，是 皮损性特应性皮炎皮肤中最高诱生的趋化因子。M(IL-4)与细胞的相互作用 最近发现的第二组先天淋巴样细胞(ILC2)有助于嗜酸性粒细胞 发炎。CCR8也是小鼠ILC2转录组的顶级签名基因。最近的IL-4Rα 抑制M(IL-4)分化的阻滞剂使治疗的临床改善显著 与CCL18抑制高度相关的难治性特应性皮炎。然而，是否以及如何 CCL18和M(IL-4)S持续慢性特应性皮炎的发病机制尚不清楚。我们已出版的和新的 初步数据使我们假设，虽然M(IL-4)S在急性炎症中具有抗炎作用， 它们在屏障界面经历致病转化，成为慢性炎症性疾病的促炎因子 炎症，部分通过CCR8途径和其他介质，以及与细胞的局部相互作用 如ILC2在皮肤中维持慢性嗜酸性过敏性炎症。为了检验这一假设，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 CCR8受体，是CCL18的功能类似物。因此，我们建议：(1)确定M(IL-4)S是否 对慢性过敏性炎症至关重要，并确定其作用机制，如果这是 由CCR8途径调节；和(2)确定ILC2如何促进慢性变态反应性炎症和 如果这是由CCR8途径介导的。我们将确定所建议研究的临床相关性。 在目标1和目标2中，使用了湿疹患者的临床标本，并将其与健康人进行比较 控制。

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.