Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses
Abstract
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 IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α 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 IRE1α-XBP1–controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-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 IRE1α-XBP1–PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 02, 2022
- Source ID
- 10.1084/jem.20221085
Entities
People
- Bikash Mishra
- Franck J Barrat
- Jeffrey Zhang-Sun
- Jessica K Gordon
- Juan R Cubillos-Ruiz
- Kimberly Showalter
- Kyriakos A Kirou
- Marie Dominique Ah Kioon
- Mary K Crow
- R. Luke Wiseman
- Robert Spiera
- Sung‐Min Hwang
- Vidyanath Chaudhary
Organizations
- Cornell University
- Hospital for Special Surgery
- National Institutes of Health
- Scleroderma Foundation
- Scleroderma Research Foundation
- Scripps Research
- The Mark Foundation for Cancer Research
- United States Department of Defense
- Weill Cornell Medicine