Division of Vascular Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, WIMR 5151, Madison, WI 53705, USA.
Int J Mol Sci. 2023 Dec 21;25(1):169. doi: 10.3390/ijms25010169.
Autophagy is a lysosomal degradation system that eliminates and recycles damaged intracellular organelles and proteins. Inflammatory macrophages play a critical role in the development of various age-related inflammatory illnesses such as abdominal aortic aneurysm, atherosclerosis, and rheumatoid arthritis; therefore, identifying the mechanisms that cause macrophage inflammation is crucial for a better understanding of and developing therapeutics for inflammatory diseases. Previous research has linked autophagy to macrophage inflammation; Atg16L1-deficient macrophages increase IL-1 and IL-18 production via inflammasome activation. In this study, however, we show an alternative pathway of macrophage inflammation in an autophagy-deficient environment. We found that inhibiting autophagy in THP1 macrophages progressively increased the expression of p65-mediated inflammatory genes. This effect was reversed by treatment with antioxidants or azd0156, an ataxia telangiectasia mutated (ATM) inhibitor. In addition, our results showed that M1 macrophages inhibit autophagy and induce DNA damage, whereas M2 macrophages activate autophagy and reduce DNA damage. Importantly, the chemical activation of autophagy or ATM inhibition during M1 polarization reduced the M1 phenotype and inflammation, whereas inhibiting autophagy during M2 polarization also reduced the M2 phenotype. Thus, our findings highlight the importance of the autophagy-ATM pathway in driving macrophage inflammation.
自噬是一种溶酶体降解系统，可消除和回收受损的细胞内细胞器和蛋白质。炎性巨噬细胞在各种与年龄相关的炎症性疾病的发展中起着至关重要的作用，如腹主动脉瘤、动脉粥样硬化和类风湿关节炎；因此，确定导致巨噬细胞炎症的机制对于更好地理解和开发炎症性疾病的治疗方法至关重要。先前的研究将自噬与巨噬细胞炎症联系起来；Atg16L1 缺陷型巨噬细胞通过炎性小体激活增加了 IL-1 和 IL-18 的产生。然而，在这项研究中，我们在自噬缺陷环境中展示了巨噬细胞炎症的另一种途径。我们发现，在 THP1 巨噬细胞中抑制自噬会逐渐增加 p65 介导的炎症基因的表达。这种效应可以通过抗氧化剂或 ATM 抑制剂 azd0156 逆转。此外，我们的结果表明，M1 巨噬细胞抑制自噬并诱导 DNA 损伤，而 M2 巨噬细胞激活自噬并减少 DNA 损伤。重要的是，在 M1 极化过程中化学激活自噬或抑制 ATM 会减少 M1 表型和炎症，而在 M2 极化过程中抑制自噬也会减少 M2 表型。因此，我们的研究结果强调了自噬-ATM 途径在驱动巨噬细胞炎症中的重要性。
