Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
Regulatory T Cell Therapies Group, Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
Immunol Cell Biol. 2022 Sep;100(8):605-623. doi: 10.1111/imcb.12562. Epub 2022 Jun 21.
Studies have highlighted a critical role for autophagy in the regulation of multiple cytokines. Autophagy inhibits the release of interleukin (IL)-1 family cytokines, including IL-1α, IL-1β and IL-18, by myeloid cells. This, in turn, impacts the release of other cytokines by myeloid cells, as well as other cells of the immune system, including IL-22, IL-23, IL-17 and interferon-γ. Here, we assessed the impact of genetic depletion of the autophagy gene Atg7 in myeloid cells on acute and chronic inflammation. In a model of acute lipopolysaccharide-induced endotoxemia, loss of autophagy in myeloid cells resulted in increased release of proinflammatory cytokines, both locally and systemically. By contrast, loss of Atg7 in myeloid cells in the Lyn model of lupus-like autoimmunity resulted in reduced systemic release of IL-6 and IL-10, with no effects on other cytokines observed. In addition, Lyn mice with autophagy-deficient myeloid cells showed reduced expression of autoantibodies relevant to systemic lupus erythematosus, including anti-histone and anti-Smith protein. In vitro, loss of autophagy, through pharmacological inhibition or small interfering RNA against Becn1, inhibited IL-10 release by human and mouse myeloid cells. This effect was evident at the level of Il10 messenger RNA expression. Our data highlight potentially important differences in the role of myeloid cell autophagy in acute and chronic inflammation and demonstrate a direct role for autophagy in the production and release of IL-10 by macrophages.
研究强调了自噬在调节多种细胞因子中的关键作用。自噬抑制髓样细胞释放白细胞介素（IL）-1 家族细胞因子，包括 IL-1α、IL-1β 和 IL-18。这反过来又影响髓样细胞以及免疫系统的其他细胞（包括 IL-22、IL-23、IL-17 和干扰素-γ）释放其他细胞因子。在这里，我们评估了在髓样细胞中遗传缺失自噬基因 Atg7 对急性和慢性炎症的影响。在急性脂多糖诱导的内毒素血症模型中，髓样细胞中自噬的缺失导致促炎细胞因子的局部和全身释放增加。相比之下，在狼疮样自身免疫的 Lyn 模型中，髓样细胞中 Atg7 的缺失导致全身性释放的 IL-6 和 IL-10 减少，而观察到对其他细胞因子没有影响。此外，髓样细胞缺乏自噬的 Lyn 小鼠表现出与全身性红斑狼疮相关的自身抗体表达减少，包括抗组蛋白和抗 Smith 蛋白。在体外，通过药理学抑制或针对 Becn1 的小干扰 RNA 缺失自噬，抑制人源和鼠源髓样细胞释放 IL-10。这种效应在 Il10 信使 RNA 表达水平上是明显的。我们的数据突出了髓样细胞自噬在急性和慢性炎症中的作用的潜在重要差异，并证明了自噬在巨噬细胞产生和释放 IL-10 中的直接作用。
