IL-8 mediates idiopathic pulmonary fibrosis mesenchymal progenitor cell fibrogenicity

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18 Scopus citations

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease, but the mechanisms driving progression remain incompletely defined. We previously reported that the IPF lung harbors fibrogenic mesenchymal progenitor cells (MPCs), which serve as a cell of origin for IPF fibroblasts. Proliferating IPF MPCs are located at the periphery of fibroblastic foci in an active cellular front at the interface between the myofibroblast-rich focus core and adjacent normal alveolar structures. Among a large set of genes that distinguish IPF MPCs from their control counterparts, we identified IL-8 as a candidate mediator of IPF MPC fibrogenicity and driver of fibrotic progression. IPF MPCs and their progeny displayed increased steady-state levels of IL-8 and its cognate receptor CXCR1 and secreted more IL-8 than did controls. IL-8 functioned in an autocrine manner promoting IPF MPC self-renewal and the proliferation and motility of IPF MPC progeny. Secreted IL-8 also functioned in a paracrine manner stimulating macrophage migration. Analysis of IPF lung tissue demonstrated codistribution of IPF MPCs with activated macrophages in the active cellular front of the fibroblastic focus. These findings indicate that IPF MPC-derived IL-8 is capable of expanding the mesenchymal cell population and recruiting activated macrophages cells to actively evolving fibrotic lesions.

Original languageEnglish (US)
Pages (from-to)L127-L136
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume314
Issue number1
DOIs
StatePublished - Jan 2018

Bibliographical note

Funding Information:
This work was supported by National Heart, Lung, and Blood Institute Grants R01-HL-125227 (to C. A. Henke) and R01-HL-125236 (to P.B. Bitterman) and funds provided by the Witowski and O’Brien families.

Funding Information:
We acknowledge the assistance of the Flow Cytometry Core Facility of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by Grant P30-CA-77598 and the University of Minnesota Imaging Center. We also acknowledge the following University of Minnesota Core Facilities: the Biomedical Genomics Center, The Minnesota Supercomputer Institute and BIONET, and the Center for Mass Spectrometry and Proteomics. This work was supported by National Heart, Lung, and Blood Institute Grants R01-HL-125227 (to C. A. Henke) and R01-HL-125236 (to P.B. Bitterman) and funds provided by the Witowski and O’Brien families.

Funding Information:
We acknowledge the assistance of the Flow Cytometry Core Facility of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by Grant P30-CA-77598 and the University of Minnesota Imaging Center. We also acknowledge the following University of Minnesota Core Facilities: the Biomedical Genomics Center, The Minnesota Supercomputer Institute and BIONET, and the Center for Mass Spectrometry and Proteomics.

Publisher Copyright:
© 2018 American Physiological Society. All rights reserved.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • Fibrotic front
  • IL-8
  • IPF mesenchymal progenitor cell
  • Macrophage

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