Inzichten in de CXCR3-ligand-as en regulatiemechanismen in reumatische aandoeningen

The interferon (IFN)-γ-inducible chemokines CXCL9 and CXCL10 govern CXCR3-dependent T-cell trafficking. While systemic levels of CXCL9, and to a lesser extent CXCL10, are increasingly used as putative markers to monitor episodes of macrophage activation syndrome (MAS) in Still's disease, their mechanistic link to disease pathology is not well defined. The functional roles and proteoform diversity of these chemokines represent major knowledge gaps. We showed that posttranslational processing of CXCL10 critically shapes its biological activity. Specifically, loss of the C-terminal residues Lys74-Pro77 markedly reduces GAG binding, CXCR3A signaling, and T-cell chemotaxis, while preserving angiostatic function, identifying the CXCL10 C-terminus as a key determinant of the functional activity of CXCL10. Longitudinal patient monitoring and analysis of large autoinflammatory disease cohorts demonstrated that circulating CXCL9 and CXCL10 discriminate Still's disease from other SAIDs and correlate with MAS severity. Mechanistic insights were obtained in a TLR9-induced mouse MAS model. Finally, we established a high-resolution top-down mass-spectrometry platform that reveals disease-specific CXCL10 proteoform signatures across rheumatic diseases. Dual-site truncated CXCL10 proteoforms dominated inflammatory tissues and fluids and reflect the local proteolytic environment. Collectively, our work moves CXCL9 and CXCL10 from putative markers to mechanistic mediators in Still's disease-associated MAS and position CXCL10 processing as a mechanistic regulator of tissue-specific inflammation.