Abstract
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vasculopathy. CXCL4 represents an early serum biomarker of severe SSc and likely contributes to inflammation via chemokine signaling pathways, but the exact role of CXCL4 in SSc pathogenesis is unclear. Here, we elucidate an unanticipated mechanism for CXCL4-mediated immune amplification in SSc, in which CXCL4 organizes “self” and microbial DNA into liquid crystalline immune complexes that amplify TLR9-mediated plasmacytoid dendritic cell (pDC)-hyperactivation and interferon-α production. Surprisingly, this activity does not require CXCR3, the CXCL4 receptor. Importantly, we find that CXCL4-DNA complexes are present in vivo and correlate with type I interferon (IFN-I) in SSc blood, and that CXCL4-positive skin pDCs coexpress IFN-I-related genes. Thus, we establish a direct link between CXCL4 overexpression and the IFN-I-gene signature in SSc and outline a paradigm in which chemokines can drastically modulate innate immune receptors without being direct agonists.
Highlights
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vasculopathy
We discovered how CXCL4, a molecule overexpressed in SSc, in several other chronic conditions[39,40,41,42], and during physiological immune responses to infections/trauma, drastically amplifies IFN-I production by breaking immune tolerance to self-DNA
We identify a novel pathway in which CXCL4 organizes DNA into liquid-crystalline immune complexes with inter-DNA spacings optimal for TLR9 amplification
Summary
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vasculopathy. We elucidate an unanticipated mechanism for CXCL4mediated immune amplification in SSc, in which CXCL4 organizes “self” and microbial DNA into liquid crystalline immune complexes that amplify TLR9-mediated plasmacytoid dendritic cell (pDC)-hyperactivation and interferon-α production This activity does not require CXCR3, the CXCL4 receptor. These data identify a direct mechanistic link between CXCL4 overexpression and the IFN-I signature in SSc, consistent with a general conceptual framework in which immune activation is modulated by the supramolecular organization of CXCL4–DNA complexes These findings illuminate unexpected non-agonist functions of CXCL4 in normal immune responses and in diseases characterized by local or systemic hyperexpression of CXCL4, including autoimmune diseases, chronic infections, wound healing, traumas, and cancer[14]
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