1. Academic Validation
  2. Chemokines form nanoparticles with DNA and can superinduce TLR-driven immune inflammation

Chemokines form nanoparticles with DNA and can superinduce TLR-driven immune inflammation

  • J Exp Med. 2022 Jul 4;219(7):e20212142. doi: 10.1084/jem.20212142.
Yong Du 1 2 Marie Dominique Ah Kioon 1 Paoline Laurent 1 2 Vidyanath Chaudhary 1 2 Michael Pierides 1 Chao Yang 1 David Oliver 1 3 Lionel B Ivashkiv 1 3 4 Franck J Barrat 1 2 3
Affiliations

Affiliations

  • 1 HSS Research Institute, Hospital for Special Surgery, New York, NY.
  • 2 Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY.
  • 3 David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY.
  • 4 Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY.
Abstract

Chemokines control the migratory patterns and positioning of immune cells to organize immune responses to pathogens. However, many chemokines have been associated with systemic autoimmune diseases that have chronic IFN signatures. We report that a series of chemokines, including CXCL4, CXCL10, CXCL12, and CCL5, can superinduce type I IFN (IFN-I) by TLR9-activated plasmacytoid DCs (pDCs), independently of their respective known chemokine receptors. Mechanistically, we show that chemokines such as CXCL4 mediate transcriptional and epigenetic changes in pDCs, mostly targeted to the IFN-I pathways. We describe that chemokines physically interact with DNA to form nanoparticles that promote clathrin-mediated cellular uptake and delivery of DNA in the early endosomes of pDCs. Using two separate mouse models of skin inflammation, we observed the presence of CXCL4 associated with DNA in vivo. These data reveal a noncanonical role for chemokines to serve as nucleic acid delivery vectors to modulate TLR signaling, with implications for the chronic presence of IFN-I by pDCs in autoimmune diseases.

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