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Interleukin-6 mediates neutrophil mobilization from bone marrow in pulmonary hypertension

Abstract

Myeloid cells, such as neutrophils, are produced in the bone marrow in high quantities and are important in the pathogenesis of vascular diseases such as pulmonary hypertension (PH). Although neutrophil recruitment into sites of inflammation has been well studied, the mechanisms of neutrophil egress from the bone marrow are not well understood. Using computational flow cytometry, we observed increased neutrophils in the lungs of patients and mice with PH. Moreover, we found elevated levels of IL-6 in the blood and lungs of patients and mice with PH. We observed that transgenic mice overexpressing Il-6 in the lungs displayed elevated neutrophil egress from the bone marrow and exaggerated neutrophil recruitment to the lungs, resulting in exacerbated pulmonary vascular remodeling, and dysfunctional hemodynamics. Mechanistically, we found that IL-6-induced neutrophil egress from the bone marrow was dependent on interferon regulatory factor 4 (IRF-4)-mediated CX3CR1 expression in neutrophils. Consequently, Cx3cr1 genetic deficiency in hematopoietic cells in Il-6-transgenic mice significantly reduced neutrophil egress from bone marrow and decreased neutrophil counts in the lungs, thus ameliorating pulmonary remodeling and hemodynamics. In summary, these findings define a novel mechanism of IL-6-induced neutrophil egress from the bone marrow and reveal a new therapeutic target to curtail neutrophil-mediated inflammation in pulmonary vascular disease.

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Acknowledgements

This work was supported by National Institute of Health grants R00HL12076, R01HL143967, and R01HL142629 to P.D.; NIH grants R01 HL124021, HL 122596, HL 138437, and UH2/UH3 TR002073; and the American Heart Association Established Investigator Award 18EIA33900027 to S.Y.C.; the AHA Transformational Project Award (19TPA34910142), AHA Innovative Project Award (19IPLOI34760566) and ALA Innovation Project Award (IA-629694) to P.D.; the VMI Postdoctoral Training Program in Translational Research and Entrepreneurship in Pulmonary and Vascular Biology T32 funded by the National, Heart, Lung and Blood Institute (NHLBI) to J.F.; the AHA postdoctoral fellowship award 20POST35210088 to S.B.V.;  the American Heart Association Grant 19CDA34730030 to R.K.; and NIH Grants and R01HL135872 to B.B.G. We thank the NIH-supported microscopy resources at the Center for Biologic Imaging (NIH grant 1S10OD019973-01). We thank the Center for Organ Recovery & Education (CORE) as well as organ donors and their families for the generous donation of tissues used in this study.

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Contributions

J.F. conducted experiments, analyzed the data, and wrote the paper. J.Z., Y.Y.T., R.K., L.S., B.K., and B.B.G. conducted experiments. S.B.V., S.P.O.N., A.A., G.C.B., L.S., and B.K. conducted experiments and analyzed the data. A.W., J.S., and M.R. recruited patients and provided peripheral blood and lung samples from healthy donors and PAH patients. S.Y.C. and P.D. designed the research study, analyzed the data, and composed the paper.

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Correspondence to Stephen Y. Chan or Partha Dutta.

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Competing interests

S.Y.C. has served as a consultant for Zogenix, Aerpio, and United Therapeutics. S.Y.C. holds research grants from Actelion and Pfizer. S.Y.C. has filed patent applications regarding the targeting of metabolism in PH. The authors declare no other competing interests.

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Florentin, J., Zhao, J., Tai, YY. et al. Interleukin-6 mediates neutrophil mobilization from bone marrow in pulmonary hypertension. Cell Mol Immunol 18, 374–384 (2021). https://doi.org/10.1038/s41423-020-00608-1

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Keywords

  • neutrophil
  • IL-6
  • pulmonary hypertension
  • CX3CR1
  • inflammation

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