Type 1 interferons induce changes in core metabolism that are critical for immune function



Type 1 interferons induce changes in core metabolism that are critical for immune function

Greater understanding of the complex host responses induced by type 1 interferon (IFN) cytokines could allow new therapeutic approaches for diseases in which these cytokines are implicated. We found that in response to the Toll-like receptor-9 agonist CpGA, plasmacytoid dendritic cells (pDC) produced type 1 IFNs, which, through an autocrine type 1 IFN receptor-dependent pathway, induced changes in cellular metabolism characterized by increased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Direct inhibition of FAO and of pathways that support this process, such as fatty acid synthesis, prevented full pDC activation. Type 1 IFNs also induced increased FAO and OXPHOS in non-hematopoietic cells and were found to be responsible for increased FAO and OXPHOS in virus-infected cells. Increased FAO and OXPHOS in response to type 1 IFNs was regulated by PPARα. Our findings reveal FAO, OXPHOS and PPARα as potential targets to therapeutically modulate downstream effects of type 1 IFNs.

Wu D(武多娇), Sanin DE, Everts B, et al. Type 1 interferons induce changes in core metabolism that are critical for immune function[J]. Immunity, 2016, 44(6):1325-1336. doi: 10.1016/j.immuni.2016.06.006.

(卓乐盈译)

Ⅰ型干扰素诱导的内在代谢改变是其免疫功能的关键

随着对Ⅰ型干扰素诱导的复杂宿主反应越来越深刻地了解，科学家们在一些细胞因子相关的疾病治疗方案的研发上取得了新进展。本研究发现，在TLR-9受体激动剂CpGA的刺激下，通过自分泌Ⅰ型干扰素的受体依赖途径，浆细胞样树突状细胞(pDC)可产生Ⅰ型干扰素，后者可诱导细胞代谢发生变化，包括细胞的脂肪酸氧化(FAO)和氧化磷酸化(OXPHOS)水平增加。直接抑制脂肪酸氧化及其相关过程，如脂肪酸合成，可抑制pDC的完全激活。Ⅰ型干扰素也能促进非造血细胞和病毒感染的细胞FAO和OXPHOS的升高。PPARα参与了Ⅰ型干扰素诱导的代谢变化过程。我们的研究提示了FAO、OXPHOS、PPARα可作为潜在的Ⅰ型干扰素效应的下游干预靶点。