Archives of Toxicology

, Volume 92, Issue 4, pp 1349–1361 | Cite as

New interplay between interstitial and alveolar macrophages explains pulmonary alveolar proteinosis (PAP) induced by indium tin oxide particles

  • François Huaux
  • Valentin De Gussem
  • Astrid Lebrun
  • Yousof Yakoub
  • Mihaly Palmai-Pallag
  • Saloua Ibouraadaten
  • Francine Uwambayinema
  • Dominique Lison
Inorganic Compounds


Occupational exposure to indium tin oxide (ITO) particles has been associated with the development of severe lung diseases, including pulmonary alveolar proteinosis (PAP). The mechanisms of this lung toxicity remain unknown. Here, we reveal the respective roles of resident alveolar (Siglec-Fhigh AM) and recruited interstitial (Siglec-Flow IM) macrophages contributing in concert to the development of PAP. In mice treated with ITO particles, PAP is specifically associated with IL-1α (not GM-CSF) deficiency and Siglec-Fhigh AM (not Siglec-Flow IM) depletion. Mechanistically, ITO particles are preferentially phagocytosed and dissolved to soluble In3+ by Siglec-Flow IM. In contrast, Siglec-Fhigh AM weakly phagocytose or dissolve ITO particles, but are sensitive to released In3+ through the expression of the transferrin receptor-1 (TfR1). Blocking pulmonary Siglec-Flow IM recruitment in CCR2-deficient mice reduces ITO particle dissolution, In3+ release, Siglec-Fhigh AM depletion, and PAP formation. Restoration of IL-1-related Siglec-Fhigh AM also prevented ITO-induced PAP. We identified a new mechanism of secondary PAP development according to which metal ions released from inhaled particles by phagocytic IM disturb IL-1α-dependent AM self-maintenance and, in turn, alveolar clearance.


Tissue-resident macrophages Recruited macrophages Alveolar macrophages Inhaled particles Indium Interleukin-1α 



This work was funded by the Actions de Recherche Concertées, Fédération Wallonie Bruxelles (ARC 09/14–021), Fonds de la Recherche Scientifique (FNRS, PAPITO J.091.16), and a research Grant from Umicore (Belgium). F.H. is a Senior Research Associate with the FNRS, Belgium.

Compliance with ethical standards

Conflict of interest

The authors have no conflicting financial interests.

Supplementary material

204_2018_2168_MOESM1_ESM.docx (28 kb)
Supplementary material 1 (DOCX 28 KB)
204_2018_2168_MOESM2_ESM.pdf (393 kb)
Supplementary material 2 (PDF 392 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Louvain Centre for Toxicology and Applied Pharmacology (LTAP)Institut de Recherche Experimentale et Clinique (IREC), Université catholique de LouvainBrusselsBelgium

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