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Updated: Oct 2, 2025
Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity
Published on: June 7, 2017
PERK is a critical metabolic hub for immunosuppressive function in macrophages
Lydia N Raines1, Haoxin Zhao1, Yuzhu Wang1,2
1Department 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.
Insights
Chronic inflammation involves immunosuppression. Researchers found that protein kinase RNA-like ER kinase (PERK) signaling in macrophages drives immunosuppressive M2 activation and proliferation through serine metabolism, offering a new therapeutic target.
Area of Science:
- Immunology
- Cellular Metabolism
- Cancer Biology
Background:
- Chronic inflammation involves compensatory immunosuppression to limit tissue damage.
- Endoplasmic reticulum (ER) stress is known to enhance immune cell suppressive phenotypes.
- The molecular mechanisms linking ER stress, metabolic reprogramming, and immunosuppressive macrophages are not fully understood.
Purpose of the Study:
- To investigate the role of the PERK signaling pathway in macrophage activation and immunosuppression.
- To elucidate the connection between ER stress, metabolic reprogramming, and the function of immunosuppressive M2 macrophages.
- To explore the therapeutic potential of inhibiting PERK signaling in cancer immunotherapy.
Main Methods:
- Utilized a combination of molecular biology techniques and cellular assays to study macrophage phenotypes.
- Investigated the impact of interleukin-4 and tumor microenvironment components on macrophage signaling.
- Assessed the effects of PERK signaling modulation on macrophage metabolism, mitochondrial function, and epigenetic modifications.
- Evaluated the efficacy of PERK inhibition in combination with immune checkpoint inhibitors in a melanoma model.
Main Results:
- Interleukin-4 and tumor microenvironment stimuli activate the PERK signaling cascade in macrophages, promoting M2 activation and proliferation.
- Loss of PERK signaling impairs mitochondrial respiration and lipid oxidation essential for M2 macrophage function.
- PERK activation upregulates phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via ATF-4.
- Enhanced serine biosynthesis supports mitochondrial function and α-ketoglutarate production for epigenetic modifications.
- Inhibition of PERK reduces macrophage immunosuppressive activity and potentiates anti-tumor immunity when combined with PD-1 blockade in melanoma.
Conclusions:
- PERK signaling is a critical mediator of immunosuppressive M2 macrophage function through PSAT1-dependent serine metabolism.
- This pathway represents a novel link between ER stress and metabolic reprogramming in immunosuppressive macrophages.
- Targeting PERK signaling offers a promising strategy to enhance cancer immunotherapy efficacy, particularly in melanoma.
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