Hepcidin Is Essential for Alveolar Macrophage Function and Is Disrupted by Smoke in a Murine Chronic Obstructive Pulmonary Disease Model

J Immunol. 2020 Nov 1;205(9):2489-2498. doi: 10.4049/jimmunol.1901284. Epub 2020 Sep 21.

Abstract

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease associated with cigarette smoking. Alterations in local lung and systemic iron regulation are associated with disease progression and pathogenesis. Hepcidin, an iron regulatory peptide hormone, is altered in subjects with COPD; however, the molecular role of hepcidin in COPD pathogenesis remains to be determined. In this study, using a murine model of smoke-induced COPD, we demonstrate that lung and circulating hepcidin levels are inhibited by cigarette smoke. We show that cigarette smoke exposure increases erythropoietin and bone marrow-derived erythroferrone and leads to expanded but inefficient erythropoiesis in murine bone marrow and an increase in ferroportin on alveolar macrophages (AMs). AMs from smokers and subjects with COPD display increased expression of ferroportin as well as hepcidin. Notably, murine AMs exposed to smoke fail to increase hepcidin in response to Gram-negative or Gram-positive infection. Loss of hepcidin in vivo results in blunted functional responses of AMs and exaggerated responses to Streptococcus pneumoniae infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / metabolism
  • Cation Transport Proteins / metabolism
  • Cigarette Smoking / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Erythropoietin / metabolism
  • Hepcidins / metabolism*
  • Humans
  • Iron / metabolism
  • Lung / metabolism
  • Macrophages, Alveolar / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Peptides / metabolism
  • Pulmonary Disease, Chronic Obstructive / metabolism*
  • Smoke
  • Smoking / metabolism*

Substances

  • Cation Transport Proteins
  • Hepcidins
  • Peptides
  • Smoke
  • metal transporting protein 1
  • Erythropoietin
  • Iron