Faculty Collaboration Database

Interleukin-6 mediates neutrophil mobilization from bone marrow in pulmonary hypertension. Cell Mol Immunol 2021 Feb;18(2):374-384

Date

01/10/2021

Pubmed ID

33420357

Pubmed Central ID

PMC8027442

DOI

10.1038/s41423-020-00608-1

Scopus ID

2-s2.0-85099109147 (requires institutional sign-in at Scopus site)   31 Citations

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.

Author List

Florentin J, Zhao J, Tai YY, Vasamsetti SB, O'Neil SP, Kumar R, Arunkumar A, Watson A, Sembrat J, Bullock GC, Sanders L, Kassa B, Rojas M, Graham BB, Chan SY, Dutta P

Author

Jonathan Florentin Research Scientist II in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bone Marrow Cells
Female
Hypertension, Pulmonary
Inflammation
Interleukin-6
Lung
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neutrophil Infiltration
Neutrophils