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Tetrameric assembly disruption impairs CXCL4 chaperon ability for DNA and type I interferon immune amplification

Giuseppe Ocone1, Anna Mennella1, Immacolata Pietraforte2

  • 1Istituto Superiore di Sanità, National center for Global Health, Roma, Italy.

Communications Biology
|May 19, 2026
PubMed

Insights

Chemokine CXCL4’s tetramer formation is crucial for amplifying the interferon-I response by chaperoning self-DNA to activate TLR9. Disrupting this tetramerization offers a potential therapeutic strategy for systemic sclerosis and other autoimmune diseases.

Area of Science:

  • Immunology
  • Biochemistry
  • Rheumatology

Background:

  • Chemokine (C-X-C motif) ligand 4 (CXCL4) is a biomarker in systemic sclerosis (SSc) and implicated in other chronic inflammatory diseases.
  • CXCL4 contributes to the interferon (IFN)-I signature in SSc by forming pro-inflammatory complexes with self-DNA, activating TLR9 and inducing IFN-α in plasmacytoid dendritic cells.

Purpose of the Study:

  • To investigate the structural requirements of CXCL4 for effective DNA chaperoning and TLR9 activation.
  • To explore the role of CXCL4 tetramerization in amplifying IFN-I secretion.
  • To identify potential pharmacological targets for SSc and related autoimmune conditions.

Main Methods:

  • Utilized mutated CXCL4 peptides with altered cationic charge and impaired tetramerization.
  • Assessed the impact of these mutations on DNA binding and TLR9 activation.
  • Investigated the effect of small molecules destabilizing CXCL4 tetramers on IFN-α production.

Main Results:

  • CXCL4 requires intact tetramerization and liquid crystalline structure formation to effectively chaperone DNA and amplify TLR9 responses.
  • Pre-assembly of CXCL4 into tetramers before DNA interaction is essential for robust IFN-I secretion.
  • Small molecules that disrupt CXCL4 tetramerization inhibit plasmacytoid dendritic cell IFN-α response.

Conclusions:

  • CXCL4 tetramerization is a critical functional step for its pro-inflammatory activity in autoimmune settings.
  • Targeting CXCL4 tetramerization presents a promising therapeutic avenue for systemic sclerosis and other autoimmune diseases characterized by CXCL4-DNA complexes.

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