TY - JOUR
T1 - Chemokines form nanoparticles with DNA and can superinduce TLR-driven immune inflammation
AU - Du, Yong
AU - Ah Kioon, Marie Dominique
AU - Laurent, Paoline
AU - Chaudhary, Vidyanath
AU - Pierides, Michael
AU - Yang, Chao
AU - Oliver, David
AU - Ivashkiv, Lionel B.
AU - Barrat, Franck J.
N1 - Publisher Copyright:
© 2022 Du et al.
PY - 2022/7/4
Y1 - 2022/7/4
N2 - 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.
AB - 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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U2 - 10.1084/jem.20212142
DO - 10.1084/jem.20212142
M3 - Article
C2 - 35640018
AN - SCOPUS:85131194774
SN - 0022-1007
VL - 219
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
M1 - e20212142
ER -