{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T00:23:48Z","timestamp":1793838228063,"version":"4.6.1"},"reference-count":43,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T00:00:00Z","timestamp":1672358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FOREUM","award":["2020\u20132023"],"award-info":[{"award-number":["2020\u20132023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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-\u03b1. By using monocyte-derived DCs (MDDCs) pretreated with IFN-\u03b1 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-\u03b1 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.<\/jats:p>","DOI":"10.3390\/ijms24010653","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T04:07:09Z","timestamp":1672632429000},"page":"653","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["CXCL4-RNA Complexes Circulate in Systemic Sclerosis and Amplify Inflammatory\/Pro-Fibrotic Responses by Myeloid Dendritic Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Immacolata","family":"Pietraforte","sequence":"first","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0, Department of Oncology and Molecular Medicine, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Butera","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0, National Center for Drug Research and Evaluation, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Gaddini","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0, National Center for Drug Research and Evaluation, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3870-5332","authenticated-orcid":false,"given":"Anna","family":"Mennella","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0, National Center for Drug Research and Evaluation, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Palazzo","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0, National Center for Drug Research and Evaluation, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doriana","family":"Campanile","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0, National Center for Drug Research and Evaluation, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Stefanantoni","sequence":"additional","affiliation":[{"name":"Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Riccieri","sequence":"additional","affiliation":[{"name":"Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8398-4567","authenticated-orcid":false,"given":"Roberto","family":"Lande","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0, National Center for Drug Research and Evaluation, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6924-3826","authenticated-orcid":false,"given":"Loredana","family":"Frasca","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0, National Center for Drug Research and Evaluation, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nrrheum.2014.53","article-title":"Fibrosis: A lethal component of systemic sclerosis","volume":"10","author":"Ho","year":"2014","journal-title":"Nat. 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