Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses

The chronic activation of pDCs is a key feature in multiple autoimmune diseases. This article reports that pDCs from autoimmune patients have defects in the regulation of metabolic pathways and that blocking the TCA cycle abrogates chronic IFN-I responses. Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1 alpha-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-alpha production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I-stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1 alpha-XBP1-controlled genes and promoted IFN-alpha production by pDCs. Mechanistically, IRE1 alpha-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1 alpha-XBP1-PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.