Chronic inflammation induces compensatory immunosuppression to stop inflammation and minimize tissue damage. Previous studies have shown that endoplasmic reticulum (ER) stress enhances the suppressive phenotype of immune cells; however, the molecular mechanism behind this phenomenon and how it is linked to the metabolic reprogramming of immunosuppressive macrophages remains unclear.

In March 2022, Stanley Ching-Cheng Huang's team from Case Western Reserve University published work in NI revealing that the Th2 cytokine IL-4 and the tumor microenvironment increased the activity of the protein kinase RNA-like ER kinase (PERK) signaling cascade in macrophages, promoting the activation and proliferation of immunosuppressive M2.

Loss of PERK signaling impedes mitochondrial respiration and lipid oxidation, which are critical for M2 macrophages. activation of PERK mediates upregulation of phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via the downstream transcription factor ATF-4. Increased serine biosynthesis leads to enhanced mitochondrial function and the production of α-ketoglutarate required for JMJD3-dependent epigenetic modifications. Inhibition of PERK suppressed the immunosuppressive activity of macrophages and enhanced the inhibitory effect of immune checkpoint programmed cell death protein 1 on melanoma.

The results of this study reveal for the first time an intrinsic link between PERK signaling and PSAT1-mediated serine metabolism, essential for promoting the immunosuppressive function of M2 macrophages.

来源： 李华兵课题组