{"doi":"10.3389/fimmu.2020.613278","title":"Endothelial TLR4 Expression Mediates Vaso-Occlusive Crisis in Sickle Cell Disease","abstract":"Heme, released from red blood cells in sickle cell disease (SCD), interacts with toll-like receptor 4 (TLR4) to activate NF-κB 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 Tlr4 -/- deficiency state into Townes-AA mice expressing normal human adult hemoglobin A and Townes-SS mice expressing sickle hemoglobin S. SS- Tlr4 -/- had similar complete blood counts and serum chemistries as SS- Tlr4 +/+ mice. However, SS- Tlr4 -/- mice developed significantly less microvascular stasis in dorsal skin fold chambers than SS- Tlr4 +/+ 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- Tlr4 -/- mice, we measured pro-inflammatory NF-κB and adhesion molecules in livers post-heme challenge. Compared to heme-challenged SS- Tlr4 +/+ livers, SS- Tlr4 -/- livers had lower adhesion molecule and cytokine mRNAs, NF-κB 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- Tlr4 -/- or SS- Tlr4 +/+ bone marrow into AA- Tlr4 -/- or AA- Tlr4 +/+ recipients. Hemin-stimulated microvascular stasis was significantly decreased when the recipient was AA- Tlr4 -/- . These data demonstrate that endothelial, but not hematopoietic, TLR4 expression is necessary to initiate vaso-occlusive physiology in SS mice.","journal":"Frontiers in Immunology","year":2021,"id":163759,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":683819,"name":"Fuad Abdullah","orcid":"0000-0002-2248-9439","position":1,"is_corresponding":false},{"id":461709,"name":"Chunsheng Chen","orcid":"0009-0000-2094-3194","position":2,"is_corresponding":false},{"id":644132,"name":"Rachel Kirchner","orcid":"0000-0001-9925-8009","position":3,"is_corresponding":false},{"id":683820,"name":"Dormarie E. Rivera-Rodriguez","orcid":"0000-0002-2091-4104","position":4,"is_corresponding":false},{"id":462631,"name":"Zachary Monroe Kiser","orcid":null,"position":5,"is_corresponding":false},{"id":446632,"name":"Aithanh Nguyen","orcid":null,"position":6,"is_corresponding":false},{"id":52428,"name":"Ping Zhang","orcid":"0000-0001-9163-6191","position":7,"is_corresponding":false},{"id":461663,"name":"Julia Nguyen","orcid":"0009-0009-4715-5150","position":8,"is_corresponding":false},{"id":294762,"name":"Robert P. Hebbel","orcid":"0000-0002-0660-7933","position":9,"is_corresponding":false},{"id":294763,"name":"John D. Belcher","orcid":"0000-0001-5536-2752","position":10,"is_corresponding":false},{"id":294764,"name":"Gregory M. Vercellotti","orcid":"0000-0003-1324-0831","position":11,"is_corresponding":false},{"id":420383,"name":"Joan D. Beckman","orcid":"0000-0001-7903-944X","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-18T23:45:22.477398Z","pmid":"33542720","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}