Respiratory Research (Jan 2022)

Iron in airway macrophages and infective exacerbations of chronic obstructive pulmonary disease

  • Terence Ho,
  • Matthew Nichols,
  • Gayatri Nair,
  • Katherine Radford,
  • Melanie Kjarsgaard,
  • Chynna Huang,
  • Anurag Bhalla,
  • Nicola Lavigne,
  • Manali Mukherjee,
  • Michael Surette,
  • Joseph Macri,
  • Parameswaran Nair

DOI
https://doi.org/10.1186/s12931-022-01929-7
Journal volume & issue
Vol. 23, no. 1
pp. 1 – 9

Abstract

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Abstract Background Excess pulmonary iron has been implicated in the pathogenesis of lung disease, including asthma and COPD. An association between higher iron content in sputum macrophages and infective exacerbations of COPD has previously been demonstrated. Objectives To assess the mechanisms of pulmonary macrophage iron sequestration, test the effect of macrophage iron-loading on cellular immune function, and prospectively determine if sputum hemosiderin index can predict infectious exacerbations of COPD. Methods Intra- and extracellular iron was measured in cell-line-derived and in freshly isolated sputum macrophages under various experimental conditions including treatment with exogenous IL-6 and hepcidin. Bacterial uptake and killing were compared in the presence or absence of iron-loading. A prospective cohort of COPD patients with defined sputum hemosiderin indices were monitored to determine the annual rate of severe infectious exacerbations. Results Gene expression studies suggest that airway macrophages have the requisite apparatus of the hepcidin-ferroportin axis. IL-6 and hepcidin play roles in pulmonary iron sequestration, though IL-6 appears to exert its effect via a hepcidin-independent mechanism. Iron-loaded macrophages had reduced uptake of COPD-relevant organisms and were associated with higher growth rates. Infectious exacerbations were predicted by sputum hemosiderin index (β = 0.035, p = 0.035). Conclusions We demonstrate in-vitro and population-level evidence that excess iron in pulmonary macrophages may contribute to recurrent airway infection in COPD. Specifically, IL-6-dependent iron sequestration by sputum macrophages may result in immune cell dysfunction and ultimately lead to increased frequency of infective exacerbation.

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