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

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

The Journal of experimental medicine (2022-06-01)
Yong Du, Marie Dominique Ah Kioon, Paoline Laurent, Vidyanath Chaudhary, Michael Pierides, Chao Yang, David Oliver, Lionel B Ivashkiv, Franck J Barrat
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
PF-4 from mouse, recombinant, expressed in E. coli, ≥98% (SDS-PAGE), ≥98% (HPLC), suitable for cell culture
Supelco
Chlorpromazine hydrochloride, VETRANAL®, analytical standard
Sigma-Aldrich
PF-4 (CXCL4) human, recombinant, expressed in E. coli, ≥98% (SDS-PAGE), ≥98% (HPLC), suitable for cell culture
Roche
DNase I, grade II, from bovine pancreas