PERK is a critical metabolic hub for immunosuppressive function in macrophages
Authors: Haoxin Zhao
Pu-Ste Liu
Hector Gallart-Ayala
Wei Cao
Yuzhu Wang
Ping-Chih Ho
Julijana Ivanisevic
Lydia N Raines
Heng-Yi Chen
Ana Alamonte-Loya
Yeojung Koh
Chan-Wang Jerry Lio
Pei-Chun Hsueh
Stanley Ching-Cheng Huang
Journal: Nature Immunology (2022)
Discipline: IMMUNOLOGY
Keywords: Chronic inflammation; immunosuppression; endoplasmic reticulum stress; macrophages; interleukin-4
Affiliations: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA., Metabolomics Service and Research Unit, University of Lausanne, Lausanne, Switzerland., Department of Oncology, University of Lausanne, Epalinges, Switzerland., Institute of Cellular and System Medicine, National Health Research Institute, Miaoli, Taiwan., Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA. .

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. 

Retracted: No

PubPeer comments:
 This is a nice work investigating how PERK ATF4 augments immunosuppressive activities of macrophages. However, there are several concerns regarding tumor experiments shown in Figure 8. First of all, animal research guidelines clearly state that tumors in mice should not exceed 1.2u2009cm diameter (1800-2000 mm3). Clearly, some mice had oversized tumors in Figure 8i ( 3000-4000 mm3). Has the authors institute approved these experiments? Please see the following article. https: scienceintegritydigest.com 2020 05 07 animal-ethics-misconduct-mice-with-very-large-tumors Secondly, in Figure 8a and 8h, authors tested inhibitors in the B16F10 melanoma model. In many published papers, B16F10 tumors reach the maximum allowable size 14-18 days after tumor challenge. Indeed, results shown in Figure 8a (vehicle) are consistent with these published results. However, these authors continued to monitor tumor growth until day 30 in survival experiments in Figure 8h. These results also suggest that these mice had very large tumors beyond the ethically approved limit. Lastly, tumor growth in Figure 8i (control Ig group) looks very abnormal. I have never seen papers showing such a dramatic increase of tumor size within 2 days (Day 14: 1000 mm3, and Day 16: 5000 mm3). Tumor growth in the control group (control IgG) looks very different from results shown in Figure 8a or previously published results in B16F10. It seems that the combination effect may be exaggerated due to the abnormally large tumor size in control group.![file] ,