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 s...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.展开更多
基金This work was supported by National Institute of Health grants R00HL12076,R01HL143967, and R01HL142629 to P.D.NIH grants R01 HL124021, HL 122596, HL138437, and UH2/UH3 TR002073+6 种基金and the American Heart Association EstablishedInvestigator Award 18EIA33900027 to S.Y.C.the AHA Transformational Project Award(19TPA34910142), AHA Innovative Project Award (19IPLOI34760566) and ALAInnovation Project Award (IA-629694) to P.D.the VMI PostdcKtoral Training Programin Translational Research and Entrepreneurship in Pulmonary and Vascular BiologyT32 funded by the National, Heart, Lung and Blood Institute (NHLBI) to J.F.the AHApostdoctoral fellowship award 20POST35210088 to S.B.V.the American HeartAssociation Grant 19CDA34730030 to R.K.NIH Grants and R01HL135872 to B.B.G.We thank the NIH-supported microscopy resources at the Center for Biologic Imaging(NIH grant 1 SI 0OD019973-01).
文摘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.
