{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:56:33Z","timestamp":1787032593925,"version":"build-2736575974"},"posted":{"date-parts":[[2026,1,25]]},"group-title":"Immunology","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T00:00:00Z","timestamp":1769299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Ascending thoracic aortic dissection (ATAD) is characterized by extensive macrophage (M\u03a6) accumulation and profound inflammation; however, the mechanisms sustaining pro-inflammatory M\u03a6 activation remain incompletely defined. Emerging evidence indicates that epigenetically generated immune memory drives innate immune cells toward persistent inflammatory states. In this study, we investigated whether epigenetic reprogramming governs M\u03a6 phenotypic fate and contributes to ATAD pathogenesis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We performed single-cell RNA sequencing of human ascending aortic tissues from controls, patients with ascending thoracic aortic aneurysm (ATAA), and patients with acute ascending thoracic aortic dissection (ATAD). We also performed integrated single-cell RNA sequencing, single-cell ATAC sequencing, and spatial transcriptomics in an angiotensin II (Ang II)\u2013infused mouse model. The role of the STING\u2013IRF3 signaling axis in M\u03a6 epigenetic programming was examined using M\u03a6-\n                    <jats:italic>\n                      Sting\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    and M\u03a6-\n                    <jats:italic>\n                      Irf3\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    mice.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    In human and mouse aortic tissues, we identified multiple functional M\u03a6 populations including pro-inflammatory, phagocytic\/anti-inflammatory, proliferative, and reparative\/healing M\u03a6s. Aortic M\u03a6s in both sporadic ATAD patients and Ang II\u2013induced ATAD mice exhibited a pronounced pro-inflammatory bias with enhanced differentiation toward pro-inflammatory M\u03a6s and impaired differentiation toward phagocytic\/anti-inflammatory states. Pro-inflammatory M\u03a6s were particularly abundant in dissection sites, whereas phagocytic M\u03a6s were enriched in discrete adventitial niches. Origin analyses revealed a substantial increase in\n                    <jats:italic>CCR2<\/jats:italic>\n                    \u207a recruited M\u03a6s within the aortic wall, which preferentially differentiated into pro-inflammatory M\u03a6s. In contrast,\n                    <jats:italic>LYVE1<\/jats:italic>\n                    \u207a resident M\u03a6s\u2014 predominantly biased toward phagocytic phenotypes\u2014were markedly depleted in ATAD. Single-cell ATAC sequencing identified coordinated chromatin remodeling with increased accessibility at pro-inflammatory gene loci and decreased accessibility at phagocytic gene loci. Among candidate transcriptional regulators identified, IRF family TFs, including IRF3 emerged as unique factors capable of simultaneously promoting pro-inflammatory gene programs while suppressing phagocytic gene expression.\n                  <\/jats:p>\n                  <jats:p>\n                    Mechanistically, STING\u2013IRF3 signaling orchestrates this biased transcriptional state, likely through coordinated BRG1-dependent chromatin opening at pro-inflammatory gene loci and chromatin closing at phagocytic\/anti-inflammatory gene loci. M\u03a6 specific\n                    <jats:italic>\n                      Sting\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      Irf3\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    mice exhibited attenuated inflammatory reprogramming and reduced aortic destruction and dissection.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings identify STING\u2013IRF3\u2013mediated epigenetic programming of M\u03a6s as a fundamental mechanism driving aortic inflammation and ATAD development. Targeting M\u03a6 epigenetic programming may represent a promising therapeutic strategy to prevent aortic dissection.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphic Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"701198v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.22.701198","type":"posted-content","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T05:35:12Z","timestamp":1769405712000},"source":"Crossref","is-referenced-by-count":2,"title":["Epigenetic Programming of Macrophage Phenotypes by STING\u2013IRF3 Drives Inflammation in Ascending Thoracic Aortic Dissection"],"prefix":"10.64898","author":[{"given":"Bowen","family":"Li","sequence":"first","affiliation":[{"name":"Division of Cardiothoracic Surgery, Michael E. 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