Immunoregulation Laboratory, Research Centre of University of Montreal Hospital, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Immunoregulation Laboratory, Research Centre of University of Montreal Hospital, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Columbia Center for Translational Immunology (CCTI), Columbia University Medical Center (CUMC), New York, New York, USA.
J Invest Dermatol. 2021 Jul;141(7):1707-1718.e9. doi: 10.1016/j.jid.2021.01.005. Epub 2021 Jan 30.
Cellular sources of IL-23 and IL-17A driving skin inflammation in psoriasis remain unclear. Using high-dimensional unsupervised flow cytometry analysis, mononuclear phagocytes and T cells were examined in the same lesions of patients before and during guselkumab (IL-23p19 blocker) or secukinumab (IL-17A blocker) treatment. Among CD11cHLA-DR mononuclear phagocytes, CD64CD163CD14CD1cCD1a inflammatory monocyte‒like cells were the predominant IL-23-producing cells and, together with CD64CD163CD14IL-23p19TNF-α inflammatory dendritic cell‒like cells, were increased in lesional compared with those in nonlesional skin taken from the same patient. Within T cells, CD8CD49a and/or CD103 tissue-resident memory T cells, CD4CD25FoxP3 regulatory T cells, and CD4CD49aCD103 T cells were increased. Moreover, CD4CD49aCD103 T cells and the relatively rare CD8 memory T cells equally contributed to IL-17A production. Both treatments decreased the frequencies of inflammatory monocyte‒like, inflammatory dendritic cell‒like, and CD4CD49aCD103 T cells. In contrast, guselkumab reduced memory T cells while maintaining regulatory T cells and vice versa for secukinumab. Neither drug modified the frequencies of IL-17AIL17F/ CD4 or CD8 T cells. This study reveals the identity of the major IL-23 mononuclear phagocyte and IL-17 T-cell subsets in psoriatic skin lesions and paves the way for a better understanding of the mode of action of drugs targeting the IL-23/IL-17A pathway in psoriasis.
细胞来源的 IL-23 和 IL-17A 驱动银屑病皮肤炎症尚不清楚。使用高维无监督流式细胞术分析，在古塞库单抗（IL-23p19 阻断剂）或司库奇尤单抗（IL-17A 阻断剂）治疗前和治疗期间，在同一患者的皮损中检查单核细胞和 T 细胞。在 CD11cHLA-DR 单核细胞中，CD64CD163CD14CD1cCD1a 炎性单核细胞样细胞是主要的 IL-23 产生细胞，与 CD64CD163CD14IL-23p19TNF-α 炎性树突状细胞样细胞一起，与来自同一患者的非皮损皮肤相比，在皮损中增加。在 T 细胞中，CD8CD49a 和/或 CD103 组织驻留记忆 T 细胞、CD4CD25FoxP3 调节性 T 细胞和 CD4CD49aCD103 T 细胞增加。此外，CD4CD49aCD103 T 细胞和相对罕见的 CD8 记忆 T 细胞同样有助于 IL-17A 的产生。两种治疗方法均降低了炎性单核细胞样细胞、炎性树突状细胞样细胞和 CD4CD49aCD103 T 细胞的频率。相比之下，古塞库单抗减少了记忆 T 细胞，而维持了调节性 T 细胞，司库奇尤单抗则反之。两种药物均未改变 IL-17AIL17F/CD4 或 CD8 T 细胞的频率。本研究揭示了银屑病皮损中主要的 IL-23 单核细胞和 IL-17 T 细胞亚群的特征，并为更好地理解靶向 IL-23/IL-17A 通路的药物作用模式铺平了道路。
