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

ABSTRACT: Chemokines are chemotactic cytokines that control the migratory patterns and positioning of immune cells. Many chemokines have been associated with systemic autoimmune diseases that have chronic IFN signature. We now describe 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 also describe that chemokines physically interact with DNA to form nanoparticles which promote clathrin-mediated cellular uptake and delivery of DNA in the early endosomes of pDCs. Using two mouse models of skin inflammation, we observed the presence of CXCL4 associated with DNA in vivo. These data thus reveal a non-canonical role for chemokines to modulate TLR signaling, and extend our understanding on the mechanism associated with the chronic expression of IFN-I by pDCs in autoimmune diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202333 | GEO | 2022/05/24

REPOSITORIES: GEO

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