<i>Regulation of plasmacytoid dendritic cells by</i>ER stress-mediated metabolic responses

Abstract Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced pDCs, which inversely correlated with IFN-I–stimulated expression. CXCL4, a chemokine highly secreted downregulated IRE1α-XBP1–controlled genes promoted Mechanistically, activation rewired glycolysis to serine biosynthesis inducing phosphoglycerate dehydrogenase (PHGDH) This process pyruvate access tricarboxylic acid (TCA) cycle blunted mitochondrial ATP generation, are essential for pDC IFN-I responses. Notably, PHGDH pDCs from patients SLE, pharmacological blockade TCA reactions inhibited responses these patients. Hence, modulating IRE1α-XBP1–PHGDH axis may represent hitherto unexplored strategy alleviating chronic disorders.