2. Academic Validation
  3. Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses

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

  • J Exp Med. 2022 Nov 7;219(11):e20221085. doi: 10.1084/jem.20221085.
Vidyanath Chaudhary 1 2,  Marie Dominique Ah Kioon 1,  Sung-Min Hwang 3,  Bikash Mishra 1 4,  Kimberly Lakin 5,  Kyriakos A Kirou 6,  Jeffrey Zhang-Sun 6,  R Luke Wiseman 7,  Robert F Spiera 5,  Mary K Crow 1 6 8,  Jessica K Gordon 5,  Juan R Cubillos-Ruiz 3 4,  Franck J Barrat 1 4 2
Affiliations

Affiliations

  • 1 HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY.
  • 2 Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY.
  • 3 Sandra and Edward Meyer Cancer Center and Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY.
  • 4 Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY.
  • 5 Department of Medicine, Division of Rheumatology and Scleroderma and Vasculitis Center, Hospital for Special Surgery, New York, NY.
  • 6 Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, NY.
  • 7 Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA.
  • 8 Department of Medicine, Weill Cornell Medicine, New York, NY.
PMID: 36053251 DOI: 10.1084/jem.20221085
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-104040
    99.84%, IRE1 RNase抑制剂
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