Hemolysis dictates monocyte differentiation via two distinct pathways in sickle cell disease vaso-occlusion
Yunfeng Liu, … , Hui Zhong, Karina Yazdanbakhsh
Yunfeng Liu, … , Hui Zhong, Karina Yazdanbakhsh
Published July 25, 2023
Citation Information: J Clin Invest. 2023;133(18):e172087. https://doi.org/10.1172/JCI172087.
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Research Article Hematology

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.

Authors

Yunfeng Liu, Shan Su, Sarah Shayo, Weili Bao, Mouli Pal, Kai Dou, Patricia A. Shi, Banu Aygun, Sally Campbell-Lee, Cheryl A. Lobo, Avital Mendelson, Xiuli An, Deepa Manwani, Hui Zhong, Karina Yazdanbakhsh

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Figure 1

Assessment of plasma CSF-1 levels and monocyte numbers in SCD.

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Assessment of plasma CSF-1 levels and monocyte numbers in SCD. (A) Plasm...
(A) Plasma CSF-1 levels in HD (n = 13) and patients with SCD at steady state (n = 30). (B) Plasma CSF-1 levels in control and sickle mice (n = 8–10). (C) The absolute number of circulating Ly-6Chi CMo and Ly-6Clo/– PMo in sickle mice (n = 6–8) on day 3 and 5 after s.c. injection with CSF-1 (0.5 mg/kg body weight/d). (D) The absolute number of circulating Ly-6Chi CMo and Ly-6Clo/– PMo in sickle mice (n = 7–8) at 72 hours following i.p. injection with anti–CSF-1 blocking antibody (1 mg/kg body weight) or isotype antibody (1 mg/kg body weight). (E) Plasma CSF-1 levels in WT mice at 20 hours after i.v. injection of PBS as control (200 μL/20 g body weight), RBC lysate (17.5 μmol hemoglobin/kg body weight), or hemin (17.5 μmol/kg body weight) (n = 4–7). (F) Plasma CSF-1 levels in WT mice at 20 hours after i.v. injection with hemin at doses of 0, 8.8, 17.5, or 35 μmol/kg body weight (n = 3–9). (G) Plasma CSF-1 levels in WT mice at time points of 0, 6, 20, and 72 hours after i.v. injection with hemin (35 μmol/kg body weight) (n = 4–6). (H) Plasma CSF-1 levels in WT mice 20 hours after i.v. injection with PBS and hemin (17.5 μmol/kg body weight), hemin and hemopexin (17.5 μmol/kg body weight), or PBS alone (200 μL/20 g body weight) as control (n = 4–7). Each symbol represents data from an individual mouse. Data are shown as the mean ± SEM and were compared using a 2-tailed Student’s t test in A, B, and D; 2-way ANOVA with Bonferroni’s multiple comparisons in C; and 1-way ANOVA with Bonferroni’s multiple comparisons in E–H. *P < 0.05.