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

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-F-high AM) and recruited interstitial (Siglec-F-low IM) macrophages contributing in concert to the development of PAP. In mice treated with ITO particles, PAP is specifically associated with IL-1 alpha (not GM-CSF) deficiency and Siglec-F-high AM (not Siglec-F-low IM) depletion. Mechanistically, ITO particles are preferentially phagocytosed and dissolved to soluble In3+ by Siglec-F-low IM. In contrast, Siglec-F-high 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-F-low IM recruitment in CCR2-deficient mice reduces ITO particle dissolution, In3+ release, Siglec-F-high AM depletion, and PAP formation. Restoration of IL-1-related Siglec-F-high 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-1 alpha-dependent AM self-maintenance and, in turn, alveolar clearance.