Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice
Denis Bedoret, … , Pierre Lekeux, Fabrice Bureau
Denis Bedoret, … , Pierre Lekeux, Fabrice Bureau
Published November 9, 2009
Citation Information: J Clin Invest. 2009;119(12):3723-3738. https://doi.org/10.1172/JCI39717.
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Research Article Pulmonology

Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice

Abstract

The respiratory tract is continuously exposed to both innocuous airborne antigens and immunostimulatory molecules of microbial origin, such as LPS. At low concentrations, airborne LPS can induce a lung DC–driven Th2 cell response to harmless inhaled antigens, thereby promoting allergic asthma. However, only a small fraction of people exposed to environmental LPS develop allergic asthma. What prevents most people from mounting a lung DC–driven Th2 response upon exposure to LPS is not understood. Here we have shown that lung interstitial macrophages (IMs), a cell population with no previously described in vivo function, prevent induction of a Th2 response in mice challenged with LPS and an experimental harmless airborne antigen. IMs, but not alveolar macrophages, were found to produce high levels of IL-10 and to inhibit LPS-induced maturation and migration of DCs loaded with the experimental harmless airborne antigen in an IL-10–dependent manner. We further demonstrated that specific in vivo elimination of IMs led to overt asthmatic reactions to innocuous airborne antigens inhaled with low doses of LPS. This study has revealed a crucial role for IMs in maintaining immune homeostasis in the respiratory tract and provides an explanation for the paradox that although airborne LPS has the ability to promote the induction of Th2 responses by lung DCs, it does not provoke airway allergy under normal conditions.

Authors

Denis Bedoret, Hugues Wallemacq, Thomas Marichal, Christophe Desmet, Florence Quesada Calvo, Emmanuelle Henry, Rodrigue Closset, Benjamin Dewals, Caroline Thielen, Pascal Gustin, Laurence de Leval, Nico Van Rooijen, Alain Le Moine, Alain Vanderplasschen, Didier Cataldo, Pierre-Vincent Drion, Muriel Moser, Pierre Lekeux, Fabrice Bureau

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Figure 1

Phenotypic and functional comparison of IMs, AMs, and lung DCs.

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Phenotypic and functional comparison of IMs, AMs, and lung DCs. (A) The ...
(A) The percentage of IMs (F4/80+CD11c–), AMs (F4/80+CD11c+), and DCs (F4/80–CD11c+) in whole lung from BALB/c mice was determined by flow cytometry. IMs, AMs, and DCs were also stained for MHC II and CD68. (B) The percentage of F4/80+CD11c–, F4/80+CD11c+, and F4/80–CD11c+ cells in BALF from BALB/c mice. (C–E) Lung cryosections were double stained for CD11c (blue) and F4/80 (red). IMs (F4/80+CD11c–) are stained red, DCs (F4/80–CD11c+) are stained blue, and AMs (F4/80+CD11c+) are double stained. (C) Representative photographs showing some IMs, AMs, and DCs (original magnification, ×100). The average number of IMs and AMs per field was calculated. (D) Image of IMs in the vicinity of DCs (original magnification, ×100). (E) Photographs at higher magnification showing IMs, AMs, interstitial F4/80+CD11c+ macrophages, and DCs (original magnification, ×200). (F and G) Alternatively, F4/80 was stained pink rather than red. (F) Representative photographs showing some IMs (pink), DCs (blue), and AMs (purple) (original magnification, ×100). (G) Photographs at higher magnification (original magnification, ×200). (H) FACS-sorted APCs were cocultured with FITC-labeled dextran in the absence or presence of sodium azide. After 45 minutes, the uptake of fluorescent dextran was determined by flow cytometry. (I) FACS-sorted APCs (1 × 104 or 4 × 104 cells/well) were loaded with the DO11.10 OVA peptide and cocultured for 3 days with naive DO11.10 CD4+ T cells. DO11.10 T cell proliferation was assessed by [3H]thymidine uptake in a 16-hour pulse. *P < 0.05 (H and I).