[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology Veterinary medicine & animal health
Author, co-author :
Bedoret, Denis ; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
Wallemacq, Hugues ; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
Marichal, Thomas ; Université de Liège - ULiège > Département de sciences fonctionnelles > GIGA-R : Biochimie et biologie moléculaire
Desmet, Christophe ; Université de Liège - ULiège > Département de sciences fonctionnelles > GIGA-R : Biochimie et biologie moléculaire
Quesada Calvo, Florence ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Henry, E.; Université Libre de Bruxelles - ULB
Closset, Rodrigue; Université de Liège - ULiège
Dewals, Benjamin G ; Université de Liège - ULiège > Immunologie et vaccinologie
Thielen, Caroline ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Gustin, Pascal ; Université de Liège - ULiège > Département de sciences fonctionnelles > Pharmacologie, pharmacothérapie et toxicologie
de Leval, Laurence ; Centre Hospitalier Universitaire de Liège - CHU > Anatomie pathologique
Van Rooijen, N.; Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands.
Cataldo, Didier ; Université de Liège - ULiège and CHU > Laboratory of Biology of Tumors and Development, GIGA-Research
Drion, Pierre ; Université de Liège - ULiège > Services généraux (Faculté de médecine vétérinaire) > GIGA-R:Méth. expér.des anim. de labo et éth. en expér. anim.
Moser, M.; Université Libre de Bruxelles - ULB
Lekeux, Pierre ; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie - Doyen de la Faculté de Médecine vétérinaire
Bureau, Fabrice ; Université de Liège - ULiège > Département de sciences fonctionnelles > GIGA-R : Biochimie et biologie moléculaire
Akbari, O., DeKruyff, R., and Umetsu, D. 2001. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat. Immunol. 2:725-731. (Pubitemid 32747162)
Akbari, O., et al. 2002. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat. Med. 8:1024-1032. (Pubitemid 35033708)
de Heer, H., et al. 2004. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200:89-98.
Michel, O., et al. 1996. Severity of asthma is related to endotoxin in house dust. Am. J. Respir. Crit. Care Med. 154:1641-1646. (Pubitemid 26424928)
Milton, D., Johnson, D., and Park, J. 1997. Environmental endotoxin measurement: interference and sources of variation in the Limulus assay of house dust. Am. Ind. Hyg. Assoc. J. 58:861-867. (Pubitemid 127824318)
Rizzo, M., et al. 1997. Endotoxin exposure and symptoms in asthmatic children. Pediatr. Allergy Immunol. 8:121-126. (Pubitemid 28067804)
Thorn, J., and Rylander, R. 1998. Airways inflammation and glucan in a rowhouse area. Am. J. Respir. Crit. Care Med. 157:1798-1803. (Pubitemid 28311261)
Douwes, J., et al. 1999. Fungal extracellular polysaccharides in house dust as a marker for exposure to fungi: relations with culturable fungi, reported home dampness, and respiratory symptoms. J. Allergy Clin. Immunol. 103:494-500. (Pubitemid 29136304)
Douwes, J., et al. 2000. (1 - >3)-beta-D-glucan and endotoxin in house dust and peak flow variability in children. Am. J. Respir. Crit. Care Med. 162:1348-1354. (Pubitemid 30826153)
Alexis, N., et al. 2005. Acute LPS inhalation in healthy volunteers induces dendritic cell maturation in vivo. J. Allergy Clin. Immunol. 115:345-350. (Pubitemid 40215101)
Eisenbarth, S., et al. 2002. Lipopolysaccharideenhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med. 196:1645-1651. (Pubitemid 36026476)
Hammad, H., et al. 2009. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat. Med. 15:410-416.
Gereda, J., et al. 2000. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. Lancet. 355:1680-1683. (Pubitemid 30248480)
Braun-Fahrländer, C., et al. 2002. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347:869-877.
Douwes, J., et al. 2006. Does early indoor microbial exposure reduce the risk of asthma? The Prevention and Incidence of Asthma and Mite Allergy birth cohort study. J. Allergy Clin. Immunol. 117:1067-1073.
Park, J., Gold, D., Spiegelman, D., Burge, H., and Milton, D. 2001. House dust endotoxin and wheeze in the first year of life. Am. J. Respir. Crit. Care Med. 163:322-328. (Pubitemid 32158506)
Alexis, N., Lay, J., Almond, M., and Peden, D. 2004. Inhalation of low-dose endotoxin favors local T(H)2 response and primes airway phagocytes in vivo. J. Allergy Clin. Immunol. 114:1325-1331. (Pubitemid 39575885)
Thorne, P., et al. 2005. Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing. Am. J. Respir. Crit. Care Med. 172:1371-1377. (Pubitemid 43069809)
Smit, L., et al. 2008. Exposure-response analysis of allergy and respiratory symptoms in endotoxin exposed adults. Eur. Respir. J. 31:1241-1248.
Lagranderie, M., et al. 2003. Dendritic cells recruited to the lung shortly after intranasal delivery of Mycobacterium bovis BCG drive the primary immune response towards a type 1 cytokine production. Immunology. 108:352-364.
Steinman, R., and Cohn, Z. 1973. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J. Exp. Med. 137:1142-1162.
Steinman, R., and Witmer, M. 1978. Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proc. Natl. Acad. Sci. U. S. A. 75:5132-5136. (Pubitemid 9046495)
Murphy, K., Heimberger, A., and Loh, D. 1990. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science. 250:1720-1723.
Franke-Ullmann, G., et al. 1996. Characterization of murine lung interstitial macrophages in comparison with alveolar macrophages in vitro. J. Immunol. 157:3097-3104. (Pubitemid 126450070)
Lambrecht, B., et al. 2000. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Invest. 106:551-559. (Pubitemid 30666388)
Bilyk, N., and Holt, P. 1993. Inhibition of the immunosuppressive activity of resident pulmonary alveolar macrophages by granulocyte/macrophage colony- stimulating factor. J. Exp. Med. 177:1773-1777. (Pubitemid 23146144)
Iwasaki, A., and Medzhitov, R. 2004. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5:987-995. (Pubitemid 41057715)
Buelens, C., et al. 1995. Interleukin-10 differentially regulates B7-1 (CD80) and B7-2 (CD86) expression on human peripheral blood dendritic cells. Eur. J. Immunol. 25:2668-2672.
De Smedt, T., et al. 1997. Effect of interleukin-10 on dendritic cell maturation and function. Eur. J. Immunol. 27:1229-1235. (Pubitemid 27197228)
Geissmann, F., et al. 1999. TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. J. Immunol. 162:4567-4575.
Austyn, J., and Gordon, S. 1981. F4/80, a monoclonal antibody directed specifically against the mouse macrophage. Eur. J. Immunol. 11:805-815. (Pubitemid 12237981)
Tidball, J., and Wehling-Henricks, M. 2007. Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo. J. Physiol. 578:327-336. (Pubitemid 44971129)
Apte, R., Richter, J., Herndon, J., and Ferguson, T. 2006. Macrophages inhibit neovascularization in a murine model of age-related macular degeneration. PLoS Med. 3:e310.
Constant, S., et al. 2002. Resident lung antigen-presenting cells have the capacity to promote Th2 T cell differentiation in situ. J. Clin. Invest. 110:1441-1448. (Pubitemid 35396915)
Holt, P., Strickland, D., Wikström, M., and Jahnsen, F. 2008. Regulation of immunological homeostasis in the respiratory tract. Nat. Rev. Immunol. 8:142-152. (Pubitemid 351161302)
Thepen, T., Van Rooijen, N., and Kraal, G. 1989. Alveolar macrophage elimination in vivo is associated with an increase in pulmonary immune response in mice. J. Exp. Med. 170:499-509. (Pubitemid 19204277)
Thepen, T., McMenamin, C., Oliver, J., Kraal, G., and Holt, P. 1991. Regulation of immune response to inhaled antigen by alveolar macrophages: differential effects of in vivo alveolar macrophage elimination on the induction of tolerance vs. immunity. Eur. J. Immunol. 21:2845-2850.
Thepen, T., McMenamin, C., Girn, B., Kraal, G., and Holt, P. 1992. Regulation of IgE production in pre-sensitized animals: in vivo elimination of alveolar macrophages preferentially increases IgE responses to inhaled allergen. Clin. Exp. Allergy. 22:1107-1114. (Pubitemid 23011173)
Holt, P., et al. 1993. Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages. J. Exp. Med. 177:397-407. (Pubitemid 23117089)
Blussé van Oud Alblas, A., van der Linden-Schrever, B., and van Furth, R. 1981. Origin and kinetics of pulmonary macrophages during an inflammatory reaction induced by intravenous administration of heat-killed bacillus Calmette-Guérin. J. Exp. Med. 154:235-252.
Manetti, R., et al. 1993. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J. Exp. Med. 177:1199-1204.
Kalinski, P., Hilkens, C.M., Snijders, A., Snijdewint, F.G., and Kapsenberg, M.L. 1997. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J. Immunol. 159:28-35. (Pubitemid 127493681)
Schwarze, J., et al. 1998. Local treatment with IL-12 is an effective inhibitor of airway hyperresponsiveness and lung eosinophilia after airway challenge in sensitized mice. J. Allergy Clin. Immunol. 102:86-93.
Wang, S., et al. 2001. IL-12-dependent vascular cell adhesion molecule-1 expression contributes to airway eosinophilic inflammation in a mouse model of asthma-like reaction. J. Immunol. 166:2741-2749. (Pubitemid 32173516)
Meyts, I., et al. 2006. IL-12 contributes to allergen-induced airway inflammation in experimental asthma. J. Immunol. 177:6460-6470.
Demangel, C., Bertolino, P., and Britton, W. 2002. Autocrine IL-10 impairs dendritic cell (DC)-derived immune responses to mycobacterial infection by suppressing DC trafficking to draining lymph nodes and local IL-12 production. Eur. J. Immunol. 32:994-1002. (Pubitemid 34428814)
Koch, F., et al. 1996. High level IL-12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10. J. Exp. Med. 184:741-746.
Koya, T., et al. 2007. IL-10-treated dendritic cells decrease airway hyperresponsiveness and airway inflammation in mice. J. Allergy Clin. Immunol. 119:1241-1250. (Pubitemid 46654182)
Salez, L., Singer, M., Balloy, V., Créminon, C., and Chignard, M. 2000. Lack of IL-10 synthesis by murine alveolar macrophages upon lipopolysaccharide exposure. Comparison with peritoneal macrophages. J. Leukoc. Biol. 67:545-552. (Pubitemid 30679786)
Denning, T., Wang, Y., Patel, S., Williams, I., and Pulendran, B. 2007. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 8:1086-1094. (Pubitemid 47423756)
Erwig, L., and Henson, P. 2007. Immunological consequences of apoptotic cell phagocytosis. Am. J. Pathol. 171:2-8. (Pubitemid 47339220)
Martinez, F., Sica, A., Mantovani, A., and Locati, M. 2008. Macrophage activation and polarization. Front. Biosci. 13:453-461.
Sternberg, E.M. 2006. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat. Rev. Immunol. 6:318-328.
Gerber, J., and Mosser, D. 2001. Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors. J. Immunol. 166:6861-6868. (Pubitemid 32467232)
Strassmann, G., et al. 1994. Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. J. Exp. Med. 180:2365-2370. (Pubitemid 24351620)
Haskó, G., Pacher, P., Deitch, E., and Vizi, E. 2007. Shaping of monocyte and macrophage function by adenosine receptors. Pharmacol. Ther. 113:264-275. (Pubitemid 46149045)
Mosser, D.M., and Edwards, J.P. 2008. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8:958-969.
Edwards, J., Zhang, X., Frauwirth, K., and Mosser, D. 2006. Biochemical and functional characterization of three activated macrophage populations. J. Leukoc. Biol. 80:1298-1307. (Pubitemid 44904968)
Stock, P., et al. 2004. Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat. Immunol. 5:1149-1156. (Pubitemid 39549629)
van Rijt, L., et al. 2005. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201:981-991.
Stumbles, P.A., et al. 1998. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J. Exp. Med. 188:2019-2031.
Stein, R., et al. 1999. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 354:541-545.
Sigurs, N., Bjarnason, R., Sigurbergsson, F., and Kjellman, B. 2000. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am. J. Respir. Crit. Care Med. 161:1501-1507. (Pubitemid 30329018)
Panuska, J., et al. 1990. Productive infection of isolated human alveolar macrophages by respiratory syncytial virus. J. Clin. Invest. 86:113-119. (Pubitemid 20226982)
Inaba, K., et al. 1992. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony- stimulating factor. J. Exp. Med. 176:1693-1702.
Gueders, M.M., et al. 2008. A novel formulation of inhaled doxycycline reduces allergen-induced inflammation, hyperresponsiveness and remodeling by matrix metalloproteinases and cytokines modulation in a mouse model of asthma. Biochem. Pharmacol. 75:514-526.
Van Rooijen, N., and Sanders, A. 1994. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J. Immunol. Methods. 174:83-93. (Pubitemid 24297139)
