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.
View: Text | PDF
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

×

Figure 5

IL-10 secretion by IMs is required for functional paralysis of LPS-stimulated DCs.

Options: View larger image (or click on image) Download as PowerPoint
IL-10 secretion by IMs is required for functional paralysis of LPS-stimu...
(A) IMs, AMs, and lung DCs were stimulated with OVALPS. Sixteen hours later, supernatants were assayed for IL-10 and TGF-β. *P < 0.05 versus AMs and DCs. †P < 0.05 versus unstimulated IMs. (B) Lung DCs were stimulated for 16 hours with OVALPS in the presence or absence of WT or Il10–/– IMs. DCs were assayed for expression of CD40, CD80, CD86, and MHC II by FACS. MFIs are shown. Ctrl, freshly isolated DCs. *P < 0.05 versus Ctrl and OVALPS plus IMs. (C) Lung DCs were placed in fresh medium or in the supernatant of OVALPS-stimulated WT or Il10–/– IMs. DCs were treated and stained as in Figure 4B. The percentage and MFI of IL-12–positive cells were measured by FACS. (D) CFSE-labeled OVALPS-DCs, OVALPS-DCs/IMs, and OVALPS-DCs/Il10–/– IMs were injected i.t. to recipients. Control mice received PBS. Twenty-four hours later, the percentages of migrating DCs (CFSE+F4/80–CD11c+) among total MLN cells were determined by FACS. (E and F) Mice were injected with CFSE-labeled OT-II T cells. Twenty-four hours later, mice received PBS-BMDCs, OVALPS-BMDCs, OVALPS-BMDCs/IMs, or OVALPS-BMDCs/Il10–/– IMs. Three days later, proliferation of CFSE-labeled OVA-specific T cells in MLNs was measured by FACS (E). Alternatively, MLN cells were restimulated with OVA, and supernatants were assayed for IL-4 (F). (G) Mice received PBS-BMDCs, OVALPS-BMDCs, OVALPS-BMDCs/IMs, or OVALPS-BMDCs/IL-10–/– IMs. From days 10 to 14, mice were exposed to OVA aerosols. On day 15, BALF cell numbers were determined. *P < 0.05 versus PBS-BMDCs and OVALPS-BMDCs/IMs (F and G).