The Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC 3052 Australia.
Cell Rep. 2022 Apr 19;39(3):110719. doi: 10.1016/j.celrep.2022.110719.
Metabolic adaptations can directly influence the scope and scale of macrophage activation and polarization. Here we explore the impact of type I interferon (IFNβ) on macrophage metabolism and its broader impact on cytokine signaling pathways. We find that IFNβ simultaneously increased the expression of immune-responsive gene 1 and itaconate production while inhibiting isocitrate dehydrogenase activity and restricting α-ketoglutarate accumulation. IFNβ also increased the flux of glutamine-derived carbon into the tricarboxylic acid cycle to boost succinate levels. Combined, we identify that IFNβ controls the cellular α-ketoglutarate/succinate ratio. We show that by lowering the α-ketoglutarate/succinate ratio, IFNβ potently blocks the JMJD3-IRF4-dependent pathway in GM-CSF and IL-4 activated macrophages. The suppressive effects of IFNβ on JMJD3-IRF4-dependent responses, including M2 polarization and GM-CSF-induced inflammatory pain, were reversed by supplementation with α-ketoglutarate. These results reveal that IFNβ modulates macrophage activation and polarization through control of the cellular α-ketoglutarate/succinate ratio.
代谢适应可以直接影响巨噬细胞激活和极化的范围和程度。在这里，我们探讨了 I 型干扰素（IFNβ）对巨噬细胞代谢的影响及其对细胞因子信号通路的更广泛影响。我们发现，IFNβ 同时增加了免疫反应基因 1 的表达和衣康酸的产生，同时抑制异柠檬酸脱氢酶活性并限制α-酮戊二酸的积累。IFNβ 还增加了谷氨酰胺衍生碳进入三羧酸循环的通量，以提高琥珀酸水平。综合来看，我们确定 IFNβ 控制细胞内的α-酮戊二酸/琥珀酸比值。我们表明，通过降低α-酮戊二酸/琥珀酸的比值，IFNβ 可以有效地阻断 GM-CSF 和 IL-4 激活的巨噬细胞中 JMJD3-IRF4 依赖性途径。IFNβ 对 JMJD3-IRF4 依赖性反应的抑制作用，包括 M2 极化和 GM-CSF 诱导的炎症性疼痛，可以通过补充α-酮戊二酸来逆转。这些结果表明，IFNβ 通过控制细胞内的α-酮戊二酸/琥珀酸比值来调节巨噬细胞的激活和极化。
