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

查看全文 作　　者：Jonathan [1]Florentin;Jingsi [1]Zhao;Yi-Yin [1]Tai;Sathish Babu [1]Vasamsetti;Scott P.O’[1]Neil;Rahul [2]Kumar;Anagha [1]Arunkumar;Annie [1]Watson;John [1,3]Sembrat;Grant [1,4]C.Bullock;Linda [5]Sanders;Biruk [2]Kassa;Mauricio [1,3]Rojas;Brian [5]B.Graham;Stephen [1]Y.Chan;Partha [1,6]Dutta

机构地区：[1]Center for Pulmonary Vascular Biology and Medicine,Pittsburgh Heart,Lung,Blood,and Vascular Medicine Institute,Division of Cardiology,Department of Medicine,University of Pittsburgh School of Medicine,University of Pittsburgh Medical Center,Pittsburgh,PA,15213,USA;[2]Division of Pulmonary and Critical Care Medicine,Zuckerberg San Francisco General Hospital and Trauma Center,University of California San Francisco,Building 100,2nd floor,1001 Potrero Ave,San Francisco,CA,USA;[3]Division of Pulmonary,Allergy and Critical Care Medicine,University of Pittsburgh,Pittsburgh,PA,15261,USA;[4]Division of Hematopathology,Pittsburgh Heart,Lung,Blood,and Vascular Medicine Institute University of Pittsburgh School of Medicine,University of Pittsburgh Medical Center,Pittsburgh,PA,15213,USA;[5]Department of Medicine,Anschutz Medical Campus,Building RC2,9th floor,12700 E 19th Ave,Aurora,CO,80045,USA;[6]Department of Immunology,University of Pittsburgh School of Medicine,Pittsburgh,PA,15213,USA

出　　处：《Cellular & Molecular Immunology》索引2021年第18卷第2期,共11页

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;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). 摘　　要：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. 关键词：NEUTROPHIL IL-6 pulmonary hypertension CX3CR1 INFLAMMATION

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

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