Mexico Children's Hospital, Endocrinology, Epidemiology & Nutrition Research Unit, Mexico City, Mexico.
Department of Molecular Biomedicine, Center for Research and Advanced Studies, National Polytechnic Institute (CINVESTAV), Mexico City, Mexico.
Front Immunol. 2022 Aug 18;13:979749. doi: 10.3389/fimmu.2022.979749. eCollection 2022.
Mucosal innate immunity functions as the first line of defense against invading pathogens. Members of the IL-1 family are key cytokines upregulated in the inflamed mucosa. Inflammatory cytokines are regulated by limiting their function and availability through their activation and secretion mechanisms. IL-1 cytokines secretion is affected by the lack of a signal peptide on their sequence, which prevents them from accessing the conventional protein secretion pathway; thus, they use unconventional protein secretion pathways. Here we show in mouse macrophages that LPS/ATP stimulation induces cytokine relocalization to the plasma membrane, and conventional secretion blockade using monensin or Brefeldin A triggers no IL-36γ accumulation within the cell. modeling indicates IL-36γ can pass through both the P2X7R and Gasdermin D pores, and both IL-36γ, P2X7R and Gasdermin D mRNA are upregulated in inflammation; further, experimental blockade of these receptors' limits IL-36γ release. Our results demonstrate that IL-36γ is secreted mainly by an unconventional pathway through membrane pores formed by P2X7R and Gasdermin D.
黏膜固有免疫作为抵御入侵病原体的第一道防线发挥作用。IL-1 家族成员是炎症黏膜中上调的关键细胞因子。炎症细胞因子的功能和可用性受到限制，通过其激活和分泌机制进行调节。IL-1 细胞因子的分泌受到其序列上缺乏信号肽的影响，这阻止了它们进入常规蛋白分泌途径；因此，它们使用非传统的蛋白分泌途径。在这里，我们在小鼠巨噬细胞中表明，LPS/ATP 刺激诱导细胞因子重新定位到质膜，并且使用莫能菌素或布雷菲德菌素 A 阻断常规分泌不会导致细胞内 IL-36γ 积累。建模表明 IL-36γ 可以穿过 P2X7R 和 Gasdermin D 孔，并且在炎症中 IL-36γ、P2X7R 和 Gasdermin D mRNA 均上调；此外，这些受体的实验阻断限制了 IL-36γ 的释放。我们的结果表明，IL-36γ 主要通过由 P2X7R 和 Gasdermin D 形成的膜孔的非传统途径分泌。
