{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:23:58Z","timestamp":1768508638926,"version":"3.49.0"},"posted":{"date-parts":[[2023,10,24]]},"group-title":"Immunology","reference-count":67,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,10,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Chronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Systems analyses integrating single-cell RNA-sequencing and complementary immunological approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming was assessed by integrated biochemical and genetic approaches. The inter-cellular propagation of homeostasis resolution was evaluated by co-culture assays with donor monocytes trained by 4-PBA and recipient na\u00efve monocytes. The\n                    <jats:italic>in vivo<\/jats:italic>\n                    effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high fat diet-fed\n                    <jats:italic>\n                      ApoE\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    mouse model with\n                    <jats:italic>i.p.<\/jats:italic>\n                    4-PBA administration. Furthermore, the selective efficacy of 4-PBA trained monocytes were examined by\n                    <jats:italic>i.v.<\/jats:italic>\n                    transfusion of\n                    <jats:italic>ex vivo<\/jats:italic>\n                    trained monocytes by 4-PBA into recipient high fat diet-fed\n                    <jats:italic>\n                      ApoE\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 this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 via reducing peroxisome stress and attenuating SYK-mTOR signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPAR\u03b3 neddylation mediated by TOLLIP. 4-PBA trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA trained monocytes effectively reduce atherosclerosis pathogenesis when administered\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision-therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.10.19.563200","type":"posted-content","created":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T11:36:45Z","timestamp":1698147405000},"source":"Crossref","is-referenced-by-count":0,"title":["Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and 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