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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(武多嬌), 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.

(卓樂(lè)盈譯)

Ⅰ型干擾素誘導(dǎo)的內(nèi)在代謝改變是其免疫功能的關(guān)鍵

隨著對(duì)Ⅰ型干擾素誘導(dǎo)的復(fù)雜宿主反應(yīng)越來(lái)越深刻地了解，科學(xué)家們?cè)谝恍┘?xì)胞因子相關(guān)的疾病治療方案的研發(fā)上取得了新進(jìn)展。本研究發(fā)現(xiàn)，在TLR-9受體激動(dòng)劑CpGA的刺激下，通過(guò)自分泌Ⅰ型干擾素的受體依賴(lài)途徑，漿細(xì)胞樣樹(shù)突狀細(xì)胞(pDC)可產(chǎn)生Ⅰ型干擾素，后者可誘導(dǎo)細(xì)胞代謝發(fā)生變化，包括細(xì)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關(guān)過(guò)程，如脂肪酸合成，可抑制pDC的完全激活。Ⅰ型干擾素也能促進(jìn)非造血細(xì)胞和病毒感染的細(xì)胞FAO和OXPHOS的升高。PPARα參與了Ⅰ型干擾素誘導(dǎo)的代謝變化過(guò)程。我們的研究提示了FAO、OXPHOS、PPARα可作為潛在的Ⅰ型干擾素效應(yīng)的下游干預(yù)靶點(diǎn)。