{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:27:55Z","timestamp":1791473275245,"version":"4.3.4"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T00:00:00Z","timestamp":1611014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Heme, released from red blood cells in sickle cell disease (SCD), interacts with toll-like receptor 4 (TLR4) to activate NF-\u03baB leading to the production of cytokines and adhesion molecules which promote inflammation, pain, and vaso-occlusion. In SCD, TLR4 inhibition has been shown to modulate heme-induced microvascular stasis and lung injury. We sought to delineate the role of endothelial verses hematopoietic TLR4 in SCD by developing a TLR4 null transgenic sickle mouse. We bred a global <jats:italic>Tlr4<jats:sup>-\/-<\/jats:sup><\/jats:italic> deficiency state into Townes-AA mice expressing normal human adult hemoglobin A and Townes-SS mice expressing sickle hemoglobin S. SS-<jats:italic>Tlr4<jats:sup>-\/-<\/jats:sup><\/jats:italic> had similar complete blood counts and serum chemistries as SS-<jats:italic>Tlr4<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice. However, SS-<jats:italic>Tlr4<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice developed significantly less microvascular stasis in dorsal skin fold chambers than SS-<jats:italic>Tlr4<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice in response to challenges with heme, lipopolysaccharide (LPS), and hypoxia\/reoxygenation (H\/R). To define a potential mechanism for decreased microvascular stasis in SS-<jats:italic>Tlr4<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice, we measured pro-inflammatory NF-\u03baB and adhesion molecules in livers post-heme challenge. Compared to heme-challenged SS-<jats:italic>Tlr4<\/jats:italic><jats:sup>+\/+<\/jats:sup> livers, SS-<jats:italic>Tlr4<\/jats:italic><jats:sup>-\/-<\/jats:sup> livers had lower adhesion molecule and cytokine mRNAs, NF-\u03baB phospho-p65, and adhesion molecule protein expression. Furthermore, lung P-selectin and von Willebrand factor immunostaining was reduced. Next, to establish if endothelial or hematopoietic cell TLR4 signaling is critical to vaso-occlusive physiology, we created chimeric mice by transplanting SS-<jats:italic>Tlr4<\/jats:italic><jats:sup>-\/-<\/jats:sup> or SS-<jats:italic>Tlr4<\/jats:italic><jats:sup>+\/+<\/jats:sup> bone marrow into AA-<jats:italic>Tlr4<\/jats:italic><jats:sup>-\/-<\/jats:sup> or AA-<jats:italic>Tlr4<\/jats:italic><jats:sup>+\/+<\/jats:sup> recipients. Hemin-stimulated microvascular stasis was significantly decreased when the recipient was AA-<jats:italic>Tlr4<jats:sup>-\/-<\/jats:sup><\/jats:italic>. These data demonstrate that endothelial, but not hematopoietic, TLR4 expression is necessary to initiate vaso-occlusive physiology in SS mice.<\/jats:p>","DOI":"10.3389\/fimmu.2020.613278","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T04:38:15Z","timestamp":1611031095000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":35,"title":["Endothelial TLR4 Expression Mediates Vaso-Occlusive Crisis in Sickle Cell Disease"],"prefix":"10.3389","volume":"11","author":[{"given":"Joan 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