CXCL4-RNA Complexes Circulate in Systemic Sclerosis and Amplify Inflammatory/Pro-Fibrotic Responses by Myeloid
Immacolata Pietraforte1, Alessia Butera2, Lucia Gaddini2
1Istituto Superiore di Sanità, Department of Oncology and Molecular Medicine, 00161 Rome, Italy.
Abstract:
CXCL4 is an important biomarker of systemic sclerosis (SSc), an incurable autoimmune disease characterized by vasculopathy and skin/internal organs fibrosis. CXCL4 contributes to the type I interferon (IFN-I) signature, typical of at least half of SSc patients, and its presence is linked to an unfavorable prognosis. The mechanism implicated is CXCL4 binding to self-DNA, with the formation of complexes amplifying TLR9 stimulation in plasmacytoid dendritic cells (pDCs). Here, we demonstrate that, upon binding to self-RNA, CXCL4 protects the RNA from enzymatic degradation. As a consequence, CXCL4-RNA complexes persist in vivo. Indeed, we show for the first time that CXCL4-RNA complexes circulate in SSc plasma and correlate with both IFN-I and TNF-α. By using monocyte-derived DCs (MDDCs) pretreated with IFN-α as a model system (to mimic the SSc milieu of the IFN-I signature), we demonstrate that CXCL4-RNA complexes induce MDDC maturation and increase, in particular, pro-inflammatory TNF-α as well as IL-12, IL-23, IL-8, and pro-collagen, mainly in a TLR7/8-dependent but CXCR3-independent manner. In contrast, MDDCs produced IL-6 and fibronectin independently in their CXCL4 RNA-binding ability. These findings support a role for CXCL4-RNA complexes, besides CXCL4-DNA complexes, in immune amplification via the modulation of myeloid DC effector functions in SSc and also during normal immune responses.
Insights
Chemokine CXCL4 binds self-RNA, forming complexes that persist in systemic sclerosis (SSc) patients. These CXCL4-RNA complexes amplify inflammation and immune responses, contributing to SSc pathogenesis.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Systemic sclerosis (SSc) is an incurable autoimmune disease marked by fibrosis and vasculopathy.
- CXCL4 is a key biomarker in SSc, associated with a poor prognosis and the type I interferon (IFN-I) signature.
- Previous research implicated CXCL4-DNA complexes in TLR9 stimulation in plasmacytoid dendritic cells (pDCs).
Purpose of the Study:
- To investigate the role of CXCL4 in binding to self-RNA.
- To determine the in vivo presence and effects of CXCL4-RNA complexes in SSc.
- To elucidate the mechanisms by which CXCL4-RNA complexes modulate myeloid dendritic cell (DC) function.
Main Methods:
- Analysis of CXCL4-RNA complex formation and stability.
- Detection and quantification of circulating CXCL4-RNA complexes in SSc plasma.
- In vitro studies using monocyte-derived DCs (MDDCs) stimulated with IFN-α and CXCL4-RNA complexes.
- Assessment of cytokine production (TNF-α, IL-12, IL-23, IL-8, IL-6) and pro-collagen expression.
- Investigation of TLR7/8 and CXCR3 dependency.
Main Results:
- CXCL4 binding to self-RNA protects RNA from degradation, forming persistent CXCL4-RNA complexes in vivo.
- Circulating CXCL4-RNA complexes were detected in SSc plasma and correlated with IFN-I and TNF-α levels.
- CXCL4-RNA complexes induced MDDC maturation, increasing pro-inflammatory cytokines (TNF-α, IL-12, IL-23, IL-8) and pro-collagen.
- These effects were primarily mediated by TLR7/8, independent of CXCR3.
- MDDCs produced IL-6 and fibronectin independently of CXCL4-RNA binding.
Conclusions:
- CXCL4-RNA complexes, alongside CXCL4-DNA complexes, contribute to immune amplification in SSc.
- These complexes modulate myeloid DC effector functions, impacting disease pathogenesis.
- Findings suggest a broader role for CXCL4-RNA interactions in SSc and normal immune responses.
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