{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:58:26Z","timestamp":1785437906829,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,15]]},"group-title":"Immunology","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL137799"],"award-info":[{"award-number":["HL137799"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL156856"],"award-info":[{"award-number":["HL156856"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["TPA97002"],"award-info":[{"award-number":["TPA97002"]}],"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Cigarette smoking (CS) is a major risk factor for cardiovascular disease (CVD) through chronic inflammation. While its pulmonary effects are well established, the mechanisms linking lung inflammation to vascular injury remain unclear. Because neutrophils are early responders to CS-induced inflammation, we hypothesized that they drive systemic myelopoiesis and vascular inflammation via alarmin release.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Wild-type (WT) mice were exposed to inhaled CS or orally administered cigarette smoke extract (CSE). Immune cell composition in lung, bronchoalveolar lavage fluid (BALF), blood, spleen, and bone marrow (BM) was assessed by flow cytometry. Hematopoietic stem and progenitor cell (HSPC) proliferation, reactive oxygen species (ROS) production, and S100A8\/A9 release were quantified. Atherosclerosis progression was evaluated in\n                    <jats:italic>Ldlr<\/jats:italic>\n                    <jats:sup>\u207b<\/jats:sup>\n                    <jats:italic>\n                      <jats:sup>\/<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\u207b<\/jats:sup>\n                    mice fed a Western diet and treated with CSE. To define the role of neutrophil-derived S100A8\/A9, bone marrow transplantation was performed using\n                    <jats:italic>S100a9<\/jats:italic>\n                    <jats:sup>\u207b<\/jats:sup>\n                    <jats:italic>\n                      <jats:sup>\/<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\u207b<\/jats:sup>\n                    or WT donors.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    CS exposure increased circulating monocytes and neutrophils through enhanced BM myelopoiesis and elevated ROS-dependent S100A8\/A9 release. Oral CSE reproduced these effects, indicating direct activation of neutrophils independent of pulmonary inflammation or lipid changes. In\n                    <jats:italic>Ldlr<\/jats:italic>\n                    <jats:sup>\u207b<\/jats:sup>\n                    <jats:italic>\n                      <jats:sup>\/<\/jats:sup>\n                    <\/jats:italic>\n                    <jats:sup>\u207b<\/jats:sup>\n                    mice, CSE accelerated atherosclerosis by promoting infiltration of inflammasome-primed neutrophils, increased IL-1\u03b2 release, and impaired macrophage efferocytosis. Hematopoietic\n                    <jats:italic>S100a9<\/jats:italic>\n                    deletion normalized myelopoiesis and reduced vascular inflammation and plaque burden.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Ingested CS components directly activate neutrophils to release S100A8\/A9, triggering myelopoiesis and vascular inflammation. These findings reveal that tobacco\u2019s cardiovascular toxicity extends beyond inhalation, implicating oral exposure as a driver of systemic inflammation and atherogenesis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Novelty and Significance<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What Is Known?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Cigarette smoking (CS) is a major risk factor for atherosclerosis, driving systemic inflammation and innate immune activation.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Neutrophils and monocytes contribute to plaque progression, but the upstream mechanisms by which CS exacerbates their pathogenic roles remain incompletely understood.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>S100A8\/A9 levels correlate with neutrophilia and cardiovascular risk in smokers, but their functional role in lesion biology is not fully defined.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What New Information Does This Article Contribute?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Identifies S100A8\/A9 as a key mediator linking CS exposure to enhanced medullary myelopoiesis, neutrophilia, and increased lesional infiltration of inflammasome-primed myeloid cells.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Demonstrates that neutrophil-derived IL-1\u03b2 impairs macrophage efferocytosis by downregulating phagocytosis receptors, thereby promoting plaque vulnerability.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Reveals that CS drives atherosclerosis even in the absence of lipid perturbations or overt pulmonary injury, highlighting a novel oral exposure\u2013vascular axis of disease propagation.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.14.682475","type":"posted-content","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T23:40:15Z","timestamp":1760571615000},"source":"Crossref","is-referenced-by-count":1,"title":["Cigarette smoke aggravates atherosclerosis by promoting the infiltration of inflammasome-primed neutrophils and disrupting macrophage function in 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