Cell surface IL-1α trafficking is specifically inhibited by interferon-γ, and associates with the membrane via IL-1R2 and GPI anchors.,European Journal of Immunology

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Cell surface IL-1α trafficking is specifically inhibited by interferon-γ, and associates with the membrane via IL-1R2 and GPI anchors.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-05-24 , DOI: 10.1002/eji.201948521
Julie N E Chan ₁ , Melanie Humphry ₁ , Lauren Kitt ₁ , Dominika Krzyzanska ₁ , Kara J Filbey ₂ , Martin R Bennett ₁ , Murray C H Clarke ₁

Affiliation

IL‐1 is a powerful cytokine that drives inflammation and modulates adaptive immunity. Both IL‐1α and IL‐1β are translated as proforms that require cleavage for full cytokine activity and release, while IL‐1α is reported to occur as an alternative plasma membrane‐associated form on many cell types. However, the existence of cell surface IL‐1α (csIL‐1α) is contested, how IL‐1α tethers to the membrane is unknown, and signaling pathways controlling trafficking are not specified. Using a robust and fully validated system, we show that macrophages present bona fide csIL‐1α after ligation of TLRs. Pro‐IL‐1α tethers to the plasma membrane in part through IL‐1R2 or via association with a glycosylphosphatidylinositol‐anchored protein, and can be cleaved, activated, and released by proteases. csIL‐1α requires de novo protein synthesis and its trafficking to the plasma membrane is exquisitely sensitive to inhibition by IFN‐γ, independent of expression level. We also reveal how prior csIL‐1α detection could occur through inadvertent cell permeabilisation, and that senescent cells do not drive the senescent‐associated secretory phenotype via csIL‐1α, but rather via soluble IL‐1α. We believe these data are important for determining the local or systemic context in which IL‐1α can contribute to disease and/or physiological processes.

中文翻译：

细胞表面 IL-1α 运输被干扰素-γ 特异性抑制，并通过 IL-1R2 和 GPI 锚与细胞膜结合。

IL-1 是一种强大的细胞因子，可驱动炎症并调节适应性免疫。IL-1α 和 IL-1β 均被翻译为前体形式，需要裂解才能获得完整的细胞因子活性和释放，而据报道 IL-1α 作为替代质膜相关形式存在于许多细胞类型中。然而，细胞表面 IL-1α (csIL-1α) 的存在存在争议，IL-1α 如何与细胞膜结合尚不清楚，控制运输的信号通路也未明确。使用稳健且经过充分验证的系统，我们表明巨噬细胞在连接 TLR 后呈现真正的 csIL-1α。Pro-IL-1α 部分通过 IL-1R2 或通过与糖基磷脂酰肌醇锚定蛋白结合与质膜结合，并可被蛋白酶切割、激活和释放。csIL-1α 需要从头合成蛋白质，它向质膜的运输对 IFN-γ 的抑制非常敏感，与表达水平无关。我们还揭示了先前的 csIL-1α 检测是如何通过无意的细胞透化作用发生的，并且衰老细胞不会通过 csIL-1α 驱动衰老相关的分泌表型，而是通过可溶性 IL-1α。我们认为这些数据对于确定 IL-1α 可能导致疾病和/或生理过程的局部或全身环境非常重要。而是通过可溶性 IL-1α。我们认为这些数据对于确定 IL-1α 可能导致疾病和/或生理过程的局部或全身环境非常重要。而是通过可溶性 IL-1α。我们认为这些数据对于确定 IL-1α 可能导致疾病和/或生理过程的局部或全身环境非常重要。

更新日期：2020-05-24

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