{"doi":"10.1172/jci172087","title":"Hemolysis dictates monocyte differentiation via two distinct pathways in sickle cell disease vaso-occlusion","abstract":"Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by painful vaso-occlusive crises (VOC) and chronic hemolysis. The mononuclear phagocyte system is pivotal to SCD pathophysiology, but the mechanisms governing monocyte/macrophage differentiation remain unknown. This study examined the influence of hemolysis on circulating monocyte trajectories in SCD. We discovered that hemolysis stimulated CSF-1 production, partly by endothelial cells via Nrf2, promoting classical monocyte (CMo) differentiation into blood patrolling monocytes (PMo) in SCD mice. However, hemolysis also upregulated CCL-2 through IFN-I, inducing CMo transmigration and differentiation into tissue monocyte-derived macrophages. Blocking CMo transmigration by anti-P selectin antibody in SCD mice increased circulating PMo, corroborating that CMo-to-tissue macrophage differentiation occurs at the expense of CMo-to-blood PMo differentiation. We observed a positive correlation between plasma CSF-1/CCL-2 ratios and blood PMo levels in patients with SCD, underscoring the clinical significance of these two opposing factors in monocyte differentiation. Combined treatment with CSF-1 and anti-P selectin antibody more effectively increased PMo numbers and reduced stasis compared with single-agent therapies in SCD mice. Altogether, these data indicate that monocyte fates are regulated by the balance between two heme pathways, Nrf2/CSF-1 and IFN-I/CCL-2, and suggest that the CSF-1/CCL-2 ratio may present a diagnostic and therapeutic target in SCD.","journal":"Journal of Clinical Investigation","year":2023,"id":341399,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":535558,"name":"Shan Su","orcid":"0000-0003-0593-9968","position":1,"is_corresponding":false},{"id":1077414,"name":"Sarah Shayo","orcid":null,"position":2,"is_corresponding":false},{"id":1077415,"name":"Weili Bao","orcid":null,"position":3,"is_corresponding":false},{"id":1077416,"name":"Mouli Pal","orcid":null,"position":4,"is_corresponding":false},{"id":1076943,"name":"Kai Dou","orcid":"0000-0003-2665-0231","position":5,"is_corresponding":false},{"id":670816,"name":"Patricia A. Shi","orcid":"0000-0002-7954-0055","position":6,"is_corresponding":false},{"id":1076944,"name":"Banu Aygün","orcid":"0000-0001-9934-5161","position":7,"is_corresponding":false},{"id":1076945,"name":"Sally A. Campbell‐Lee","orcid":"0000-0003-4157-2120","position":8,"is_corresponding":false},{"id":756991,"name":"Cheryl A. Lobo","orcid":"0000-0001-8193-8559","position":9,"is_corresponding":false},{"id":685147,"name":"Avital Mendelson","orcid":"0000-0002-1120-9593","position":10,"is_corresponding":false},{"id":88185,"name":"Xiuli An","orcid":null,"position":11,"is_corresponding":false},{"id":366912,"name":"Deepa Manwani","orcid":"0000-0003-1057-1811","position":12,"is_corresponding":false},{"id":1076946,"name":"Hui Zhong","orcid":"0000-0002-1933-3046","position":13,"is_corresponding":false},{"id":660258,"name":"Karina Yazdanbakhsh","orcid":"0000-0002-1968-0101","position":14,"is_corresponding":false},{"id":1076942,"name":"Yunfeng Liu","orcid":"0000-0002-9187-4146","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T01:11:03.393978Z","pmid":"37490346","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":[]}