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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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 4

IMs have the capacity to attenuate LPS-induced maturation and migration of antigen-loaded DCs.

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IMs have the capacity to attenuate LPS-induced maturation and migration ...
(A) Lung DCs (106 cells) from BALB/c mice were stimulated for 16 hours with OVALPS in the presence or absence of AMs (2 × 106 cells) or IMs (1 × 106 cells). DCs were then assayed for expression of CD40, CD80, CD86, and MHC II by FACS. Freshly isolated lung DCs served as control (Ctrl). MFIs are shown. (B) Lung DCs were placed in fresh medium or in the supernatant (sn) of OVALPS-stimulated IMs or AMs. DCs were then treated with OVALPS for 2 hours, incubated with Brefeldin A for an additional 5 hours, and finally stained for IL-12p40. The percentage of IL-12–positive cells was measured by FACS. (C and D) Lung DCs (2 × 104 cells) were stimulated for 16 hours with OVALPS in the presence or absence of AMs (4 × 104 cells) or IMs (2 × 104 cells). APCs were then cocultured for 72 hours with 2 × 105 DO11.10 CD4+ T cells. Unpulsed DCs were used as controls. (C) DO11.10 T cell proliferation was measured. (D) IL-4 and IL-5 were measured in the supernatants (ELISA). (E) CFSE-labeled OVALPS-DCs, OVALPS-DCs/AMs, or OVALPS-DCs/IMs were injected in the trachea of naive mice. Control mice received PBS. Twenty-four hours later, MLNs were digested and stained for F4/80 and CD11c. The percentages of migrating DCs (CFSE+F4/80–CD11c+) among total MLN cells were determined by FACS. The total numbers of migrating DCs were calculated. *P < 0.05 (A and C–E).