CCR4 拮抗剂通过抑制 Th2 细胞和 Th17 细胞的募集和扩增来减轻特应性皮炎样皮肤炎症。,International Immunology

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CCR4 拮抗剂通过抑制 Th2 细胞和 Th17 细胞的募集和扩增来减轻特应性皮炎样皮肤炎症。
International Immunology ( IF 4.8 ) Pub Date : 2023-09-05 , DOI: 10.1093/intimm/dxad019
Masako Sato ₁ , Kazuhiko Matsuo ₂ , Yoko Susami ₂ , Ayaka Yamashita ₂ , Haruko Hayasaka ₃ , Yuta Hara ₂ , Keiji Nishiwaki ₄ , Naoki Oiso _{1,

5} , Akira Kawada ₁ , Atsushi Otsuka ₁ , Takashi Nakayama ₂

Affiliation

CCR4 是辅助性 T (Th) 2 细胞和 Th17 细胞的主要转运受体，被认为是特应性皮炎 (AD) 的潜在治疗靶点。据报道，CCR4 配体 CCL17 和 CCL22 在 AD 患者的皮损中表达上调。值得注意的是，胸腺基质淋巴细胞生成素（TSLP）是 Th2 免疫反应的主要调节因子，可促进 AD 皮肤病变中 CCL17 和 CCL22 的表达。在这里，我们研究了 CCR4 在 TSLP 诱导剂 MC903 诱导的 AD 小鼠模型中的作用。将 MC903 局部应用于耳部皮肤不仅会增加 TSLP 的表达，还会增加 CCL17、CCL22、Th2 细胞因子 IL-4 和 Th17 细胞因子 IL-17A 的表达。一致地，MC903 诱导了类似 AD 的皮肤损伤，表现为表皮厚度增加；嗜酸性粒细胞、肥大细胞、2 型先天淋巴细胞、Th2 细胞和 Th17 细胞浸润增加；血清总 IgE 水平升高。我们还发现 AD 小鼠区域淋巴结 (LN) 中 Th2 细胞和 Th17 细胞的扩增增加。化合物 22 是一种 CCR4 抑制剂，可通过减少皮损和局部淋巴结中的 Th2 细胞和 Th17 细胞来改善 AD 样皮损。我们进一步证实，在来自 AD 小鼠局部淋巴结的 CD11c+ 树突状细胞 (DC) 和 CD4+ T 细胞共培养物中，化合物 22 减少了 Th2 细胞和 Th17 细胞的扩增。总的来说，CCR4 拮抗剂可能通过抑制 AD 中 Th2 细胞和 Th17 细胞的募集和扩增来发挥抗过敏作用。

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A CCR4 antagonist attenuates atopic dermatitis-like skin inflammation by inhibiting the recruitment and expansion of Th2 cells and Th17 cells.

CCR4 is a major trafficking receptor for T-helper (Th) 2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c+ dendritic cells (DCs) and CD4+ T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.

更新日期：2023-06-05

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