Journal article
Interleukin-6 mediates neutrophil mobilization from bone marrow in pulmonary hypertension
Cellular & molecular immunology, Vol.18(2), pp.374-384
02/01/2021
DOI: 10.1038/s41423-020-00608-1
PMCID: PMC8027442
PMID: 33420357
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 CX(3)CR1 expression in neutrophils. Consequently, Cx(3)cr1 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.
Details
- Title: Subtitle
- Interleukin-6 mediates neutrophil mobilization from bone marrow in pulmonary hypertension
- Creators
- Jonathan Florentin - University of Pittsburgh Medical CenterJingsi Zhao - University of Pittsburgh Medical CenterYi-Yin Tai - University of PittsburghSathish Babu Vasamsetti - University of Pittsburgh Medical CenterScott P. O'Neil - University of PittsburghRahul Kumar - San Francisco General HospitalAnagha Arunkumar - University of Pittsburgh Medical CenterAnnie Watson - University of Pittsburgh Medical CenterJohn Sembrat - University of Pittsburgh Medical CenterGrant C. Bullock - University of Pittsburgh Medical CenterLinda Sanders - University of Colorado Anschutz Medical CampusBiruk Kassa - San Francisco General HospitalMauricio Rojas - University of PittsburghBrian B. Graham - University of Colorado Anschutz Medical CampusStephen Y. Chan - University of Pittsburgh Medical CenterPartha Dutta - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Cellular & molecular immunology, Vol.18(2), pp.374-384
- DOI
- 10.1038/s41423-020-00608-1
- PMID
- 33420357
- PMCID
- PMC8027442
- NLM abbreviation
- Cell Mol Immunol
- ISSN
- 1672-7681
- eISSN
- 2042-0226
- Publisher
- CHIN SOCIETY IMMUNOLOGY
- Number of pages
- 11
- Grant note
- R01HL135872 / National Heart Lung and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) VMI Postdoctoral Training Program in Translational Research and Entrepreneurship in Pulmonary and Vascular Biology T32 - National, Heart, Lung and Blood Institute (NHLBI) IA-629694 / ALA Innovation Project Award 18EIA33900027; 19CDA34730030 / American Heart Association R01 HL124021; HL 122596; HL 138437; UH2/UH3 TR002073; R01HL135872; 1S10OD019973-01 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 19IPLOI34760566 / AHA Innovative Project Award R00HL12076; R01HL143967; R01HL142629 / National Institute of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 19TPA34910142 / AHA Transformational Project Award 20POST35210088 / AHA postdoctoral fellowship; American Heart Association
- Language
- English
- Date published
- 02/01/2021
- Academic Unit
- Pathology
- Record Identifier
- 9984697642302771
Metrics
5 Record Views