Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Leibniz Institute for Immunotherapy, University Regensburg, 93053, Regensburg, Germany.
J Mol Med (Berl). 2023 Sep;101(9):1153-1166. doi: 10.1007/s00109-023-02349-w. Epub 2023 Aug 18.
Psoriasis is a chronic inflammatory skin disease driven by the IL-23/IL-17 axis. It results from excessive activation of effector T cells, including T helper (Th) and cytotoxic T (Tc) cells, and is associated with dysfunctional regulatory T cells (Tregs). Acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme of fatty acid synthesis (FAS), directs cell fate decisions between Th17 and Tregs and thus could be a promising therapeutic target for psoriasis treatment. Here, we demonstrate that targeting ACC1 in T cells by genetic ablation ameliorates skin inflammation in an experimental model of psoriasis by limiting Th17, Tc17, Th1, and Tc1 cells in skin lesions and increasing the frequency of effector Tregs in skin-draining lymph nodes (LNs). KEY MESSAGES : ACC1 deficiency in T cells ameliorates psoriatic skin inflammation in mice. ACC1 deficiency in T cells reduces IL-17A-producing Th17/Tc17/dysfunctional Treg populations in psoriatic lesions. ACC1 deficiency in T cells restrains IFN-γ-producing Th1/Tc1 populations in psoriatic skin lesions and skin-draining LNs. ACC1 deficiency promotes activated CD44CD25 Tregs and effector CD62LCD44 Tregs under homeostasis and psoriatic conditions.
银屑病是一种由 IL-23/IL-17 轴驱动的慢性炎症性皮肤病。它是由效应 T 细胞（包括辅助性 T 细胞和细胞毒性 T 细胞）的过度激活引起的，与功能失调的调节性 T 细胞（Tregs）有关。乙酰辅酶 A 羧化酶 1（ACC1）是脂肪酸合成（FAS）的限速酶，它在 Th17 和 Tregs 之间决定细胞命运，因此可能是治疗银屑病的有前途的治疗靶点。在这里，我们证明通过基因敲除 T 细胞中的 ACC1，可以通过在皮肤损伤处限制 Th17、Tc17、Th1 和 Tc1 细胞，并增加皮肤引流淋巴结（LNs）中效应性 Tregs 的频率，从而改善银屑病实验模型中的皮肤炎症。关键信息：T 细胞中 ACC1 的缺乏可改善小鼠的银屑病皮肤炎症。T 细胞中 ACC1 的缺乏减少了银屑病病变中产生 IL-17A 的 Th17/Tc17/功能失调的 Treg 群体。T 细胞中 ACC1 的缺乏可抑制银屑病皮肤损伤和引流皮肤的 LNs 中产生 IFN-γ的 Th1/Tc1 群体。T 细胞中 ACC1 的缺乏在稳态和银屑病条件下促进激活的 CD44CD25 Tregs 和效应性 CD62LCD44 Tregs。
