Non-Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock


Hemolysis dictates monocyte differentiation via two distinct pathways in sickle cell disease vaso-occlusion.


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 SCD patients, 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 to 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.

Authors: Liu Y, Su S, Shayo S, Bao W, Pal M, Dou K, Shi PA, Aygun B, Campbell-Lee S, Lobo CA, Mendelson A, An X, Manwani D, Zhong H, Yazdanbakhsh K,
Journal: J Clin Invest . 2023 Sep 15;133(18):e172087. doi: 10.1172/JCI172087.
Year: 2023
PubMed: PMID: 37490346 (Go to PubMed)