美国凯斯西储大学医学院Stanley Ching-Cheng Huang研究组发现，PERK是巨噬细胞免疫抑制功能的关键代谢枢纽。该项研究成果发表在2022年2月28日出版的《自然—免疫学》上。

他们报道了辅助T细胞2细胞因子IL-4和肿瘤微环境增加了巨噬细胞中蛋白激酶RNA样ER激酶 (PERK) 信号级联的活性，并促进了免疫抑制性M2激活和增殖。PERK信号的丢失阻碍了对M2巨噬细胞至关重要的线粒体呼吸和脂质氧化。PERK激活通过下游转录因子ATF-4介导磷酸丝氨酸氨基转移酶1(PSAT1) 和丝氨酸生物合成的上调。

丝氨酸生物合成的增加导致JMJD3依赖性表观遗传修饰所需的线粒体功能和α-酮戊二酸产生增强。抑制PERK可抑制巨噬细胞免疫抑制活性，并可增强免疫检查点程序性细胞死亡蛋白1抑制在黑色素瘤中的功效。他们的研究结果描述了PERK信号传导和PSAT1介导的丝氨酸代谢之间先前未描述的联系，这对于促进M2巨噬细胞的免疫抑制功能至关重要。

据介绍，慢性炎症触发代偿性免疫抑制以阻止炎症并最大限度地减少组织损伤。研究表明，内质网 (ER) 应激会增强免疫细胞的抑制表型，然而，支撑这一过程的分子机制以及它如何与免疫抑制性巨噬细胞的代谢重编程联系起来仍然难以捉摸。

附：英文原文

Title: PERK is a critical metabolic hub for immunosuppressive function in macrophages

Author: Raines, Lydia N., Zhao, Haoxin, Wang, Yuzhu, Chen, Heng-Yi, Gallart-Ayala, Hector, Hsueh, Pei-Chun, Cao, Wei, Koh, Yeojung, Alamonte-Loya, Ana, Liu, Pu-Ste, Ivanisevic, Julijana, Lio, Chan-Wang Jerry, Ho, Ping-Chih, Huang, Stanley Ching-Cheng

Issue&Volume: 2022-02-28

Abstract: Chronic inflammation triggers compensatory immunosuppression to stop inflammation and minimize tissue damage. Studies have demonstrated that endoplasmic reticulum (ER) stress augments the suppressive phenotypes of immune cells; however, the molecular mechanisms underpinning this process and how it links to the metabolic reprogramming of immunosuppressive macrophages remain elusive. In the present study, we report that the helper T cell 2 cytokine interleukin-4 and the tumor microenvironment increase the activity of a protein kinase RNA-like ER kinase (PERK)-signaling cascade in macrophages and promote immunosuppressive M2 activation and proliferation. Loss of PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. PERK activation mediated the upregulation of phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via the downstream transcription factor ATF-4. Increased serine biosynthesis resulted in enhanced mitochondrial function and α-ketoglutarate production required for JMJD3-dependent epigenetic modification. Inhibition of PERK suppressed macrophage immunosuppressive activity and could enhance the efficacy of immune checkpoint programmed cell death protein 1 inhibition in melanoma. Our findings delineate a previously undescribed connection between PERK signaling and PSAT1-mediated serine metabolism critical for promoting immunosuppressive function in M2 macrophages.

DOI: 10.1038/s41590-022-01145-x

Source: https://www.nature.com/articles/s41590-022-01145-x