Key Points 4-1BBL signaling regulates metabolism and polarization in macrophages. Blocking 4-1BBL signaling alleviates the severity of psoriasis in mice. Targeting 4-1BBL signaling can be an option for treating psoriasis in patients. 4-1BBL, a member of the TNF superfamily, regulates the sustained production of inflammatory cytokines in macrophages triggered by TLR signaling. In this study, we have investigated the role of 4-1BBL in macrophage metabolism and polarization and in skin inflammation using a model of imiquimod-induced psoriasis in mice. Genetic ablation or blocking of 4-1BBL signaling by Ab or 4-1BB–Fc alleviated the pathology of psoriasis by regulating the expression of inflammatory cytokines associated with macrophage activation and regulated the polarization of macrophages in vitro. We further linked this result with macrophage by finding that 4-1BBL expression during the immediate TLR response was dependent on glycolysis, mitochondrial oxidative phosphorylation, and fatty acid metabolism, whereas the late-phase 4-1BBL–mediated sustained inflammatory response was dependent on glycolysis and fatty acid synthesis. Correlating with this, administration of a fatty acid synthase inhibitor, cerulenin, also alleviated the pathology of psoriasis. We further found that 4-1BBL–mediated psoriasis development is independent of its receptor 4-1BB, as a deficiency of 4-1BB augmented the severity of psoriasis linked to a reduced regulatory T cell population and increased IL-17A expression in γδ T cells. Additionally, coblocking of 4-1BBL signaling and IL-17A activity additively ameliorated psoriasis. Taken together, 4-1BBL signaling regulates macrophage polarization and contributes to imiquimod-induced psoriasis by sustaining inflammation, providing a possible avenue for psoriasis treatment in patients.

中文翻译：

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4-1BBL 调节巨噬细胞的极化，抑制 4-1BBL 信号可减轻咪喹莫特诱导的银屑病

关键点 4-1BBL 信号调节巨噬细胞的代谢和极化。阻断 4-1BBL 信号可减轻小鼠银屑病的严重程度。靶向 4-1BBL 信号可能是治疗患者银屑病的一种选择。4-1BBL 是 TNF 超家族的成员，可调节由 TLR 信号触发的巨噬细胞中炎性细胞因子的持续产生。在这项研究中，我们使用咪喹莫特诱导的小鼠银屑病模型研究了 4-1BBL 在巨噬细胞代谢和极化以及皮肤炎症中的作用。Ab 或 4-1BB-Fc 对 4-1BBL 信号的遗传消融或阻断通过调节与巨噬细胞活化相关的炎性细胞因子的表达并调节体外巨噬细胞的极化来缓解银屑病的病理。我们进一步将这一结果与巨噬细胞联系起来，发现在即刻 TLR 反应期间 4-1BBL 的表达依赖于糖酵解、线粒体氧化磷酸化和脂肪酸代谢，而后期 4-1BBL 介导的持续炎症反应依赖于糖酵解和脂肪酸合成。与此相关的是，脂肪酸合酶抑制剂蔚蓝素的给药也减轻了牛皮癣的病理学。我们进一步发现 4-1BBL 介导的银屑病发展与其受体 4-1BB 无关，因为 4-1BB 的缺乏会增加银屑病的严重程度，这与调节性 T 细胞数量减少和 γδ T 细胞中 IL-17A 表达增加有关. 此外，4-1BBL 信号传导和 IL-17A 活性的共同阻断可额外改善银屑病。综合起来，