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 7

IMs prevent LPS-triggered Th2 responses to innocuous inhaled antigens.

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IMs prevent LPS-triggered Th2 responses to innocuous inhaled antigens. (...
(A–G) Naive BALB/c mice were injected i.p. daily from day 1 to 3 with depleting anti-F4/80 or control isotype antibodies. (A–C) On day 2, mice received an i.t. injection of OVALPS. (A and B) On day 6, MLN cells were restimulated for 3 days with 25 μg/ml OVA. The proliferation was measured (A), and culture supernatants were assayed for IL-4 and IL-5 by ELISA (B). (C) From day 11 to 14, mice were challenged intranasally with 25 μg OVA (grade V; Sigma-Aldrich) in 50 μl PBS. On day 15, BALF was subjected to differential cell counts. (D) On day 2, IM-depleted and control mice were injected i.t. with 100 μg FITC-OVA (rather than unlabeled OVA) and 10 ng LPS. On day 3, MLNs were analyzed by flow cytometry for the presence of OVA-loaded DCs (FITC+F4/80–CD11c+). Percentages (left) and total numbers (right) of migrating DCs are shown. (E) On day 4, the percentages of T (CD3ε+, CD4+, or CD8α+ cells) and B (CD19+ cells) cells in MLNs were measured by flow cytometry. (F and G) On day 4, B and T cells were isolated from MLNs and stimulated ex vivo with agonist anti-CD40 antibodies or anti-CD3 and anti-CD28 antibodies, respectively. Control cells were left unstimulated. B cell (F) and T cell (G) proliferation was measured as [3H]thymidine incorporation during the last 16 hours of a 2-day culture. *P < 0.05 versus results obtained with isotype control antibodies (A–D).