Commun Biol. 2026 May 19. doi: 10.1038/s42003-026-10176-1. Online ahead of print.
ABSTRACT
Chemokine (C-X-C motif) ligand 4 (CXCL4), an antimicrobial chemokine with multiple effector functions, is a known biomarker in systemic sclerosis (SSc), but it also plays important roles in inflammatory bowel diseases, atopic dermatitis, psoriasis, systemic lupus erythematosus and other chronic inflammatory diseases. In SSc, the presence of CXCL4 correlates with severe disease progression: CXCL4 contributes to the interferon-(IFN)-I signature by forming pro-inflammatory liquid crystalline complexes with self-DNA, which have the capacity to activate TLR9 in a multivalent manner and potently induce IFN-α in plasmacytoid dendritic cells. Here, we show that in order to chaperone DNA to amplify TLR9 responses effectively, CXCL4 needs to retain its ability to assemble into tetramers, in addition to forming the optimal liquid crystalline structure. By comparing various mutated CXCL4 derived peptides with altered cationic charge and with ablated capacity to from stable tetramers, we find the surprising result that the physiological pre-assembly of CXCL4 into tetramers, before DNA interaction, is important for strong amplified IFN-I secretion. Most importantly, small molecules that destabilize CXCL4 tetramerization block the plasmacytoid dendritic cells IFN-α response, suggesting new pharmacological interventions in SSc, and possibly in other autoimmune conditions characterized by the presence of high CXCL4 and CXCL4-DNA complexes expression.
PMID:42156955 | DOI:10.1038/s42003-026-10176-1