[en] Living in a microbe-rich environment reduces the risk of developing asthma. Exposure of humans or mice to unmethylated CpG DNA (CpG) from bacteria reproduces these protective effects, suggesting a major contribution of CpG to microbe-induced asthma resistance. However, how CpG confers protection remains elusive. We found that exposure to CpG expanded regulatory lung interstitial macrophages (IMs) from monocytes infiltrating the lung or mobilized from the spleen. Trafficking of IM precursors to the lung was independent of CCR2, a chemokine receptor required for monocyte mobilization from the bone marrow. Using a mouse model of allergic airway inflammation, we found that adoptive transfer of IMs isolated from CpG-treated mice recapitulated the protective effects of CpG when administered before allergen sensitization or challenge. IM-mediated protection was dependent on IL-10, given that Il10-/- CpG-induced IMs lacked regulatory effects. Thus, the expansion of regulatory lung IMs upon exposure to CpG might underlie the reduced risk of asthma development associated with a microbe-rich environment.
Research center :
GIGA-I3 - Giga-Infection, Immunity and Inflammation - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Sabatel, Catherine ✱; Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Radermecker, Coraline ✱; Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Fievez, Laurence ✱; Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Paulissen, Geneviève ; Université de Liège > Département des sciences cliniques > Hépato-gastroentérologie
Chakarov, Svetoslav; Singapore Immunology Network, Agency for Science, Technology, and Research, Singapore 138648, Singapore
Fernandes, Claudia; Université de Liège - ULiège > Laboratory of Cellular and Molecular Immunology, GIGA Research
Olivier, Sabine; Université de Liège - ULiège > Laboratory of Cellular and Molecular Immunology, GIGA Research
Toussaint, Marie; Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, UK
Pirottin, Dimitri ; Université de Liège > Département des sciences fonctionnelles (DSF) > Département des sciences fonctionnelles (DSF)
Xiao, Xue ; Université de Liège > Département des maladies infectieuses et parasitaires (DMI) > Vaccinologie vétérinaire
Quatresooz, Pascale ; Université de Liège > Département des sciences biomédicales et précliniques > Histologie
Sirard, Jean-Claude; University of Lille,CHU Lille, Institut Pasteur de Lille, France > INSERM U1019, CNRSUMR8204, Center for Infection and Immunity of Lille
Cataldo, Didier ; Université de Liège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Gillet, Laurent ; Université de Liège > Département des maladies infectieuses et parasitaires (DMI) > Vaccinologie vétérinaire
Bouabe, Hicham; Babraham Institute, Cambridge CB22 3AT, UK > Laboratory of Lymphocyte Signalling and Development
Desmet, Christophe ; Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Ginhoux, Florent; Singapore Immunology Network, Agency for Science, Technology, and Research, Singapore 138648, Singapore
Marichal, Thomas ✱; Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Bureau, Fabrice ✱; Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Aziz, A., Soucie, E., Sarrazin, S., Sieweke, M.H., MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages. Science 326 (2009), 867–871.
Bain, C.C., Bravo-Blas, A., Scott, C.L., Gomez Perdiguero, E., Geissmann, F., Henri, S., Malissen, B., Osborne, L.C., Artis, D., Mowat, A.M., Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat. Immunol. 15 (2014), 929–937.
Bedoret, D., Wallemacq, H., Marichal, T., Desmet, C., Quesada Calvo, F., Henry, E., Closset, R., Dewals, B., Thielen, C., Gustin, P., et al. Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice. J. Clin. Invest. 119 (2009), 3723–3738.
Beeh, K.M., Kanniess, F., Wagner, F., Schilder, C., Naudts, I., Hammann-Haenni, A., Willers, J., Stocker, H., Mueller, P., Bachmann, M.F., Renner, W.A., The novel TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma. J. Allergy Clin. Immunol. 131 (2013), 866–874.
Bouabe, H., Liu, Y., Moser, M., Bösl, M.R., Heesemann, J., Novel highly sensitive IL-10-beta-lactamase reporter mouse reveals cells of the innate immune system as a substantial source of IL-10 in vivo. J. Immunol. 187 (2011), 3165–3176.
Braun-Fahrländer, C., Riedler, J., Herz, U., Eder, W., Waser, M., Grize, L., Maisch, S., Carr, D., Gerlach, F., Bufe, A., et al., Allergy and Endotoxin Study Team. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347 (2002), 869–877.
Broide, D., Schwarze, J., Tighe, H., Gifford, T., Nguyen, M.D., Malek, S., Van Uden, J., Martin-Orozco, E., Gelfand, E.W., Raz, E., Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice. J. Immunol. 161 (1998), 7054–7062.
Chen, L., Arora, M., Yarlagadda, M., Oriss, T.B., Krishnamoorthy, N., Ray, A., Ray, P., Distinct responses of lung and spleen dendritic cells to the TLR9 agonist CpG oligodeoxynucleotide. J. Immunol. 177 (2006), 2373–2383.
Covarrubias, A.J., Aksoylar, H.I., Yu, J., Snyder, N.W., Worth, A.J., Iyer, S.S., Wang, J., Ben-Sahra, I., Byles, V., Polynne-Stapornkul, T., et al. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. eLife, 5, 2016, e11612.
Creticos, P.S., Schroeder, J.T., Hamilton, R.G., Balcer-Whaley, S.L., Khattignavong, A.P., Lindblad, R., Li, H., Coffman, R., Seyfert, V., Eiden, J.J., Broide, D., Immune Tolerance Network Group. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N. Engl. J. Med. 355 (2006), 1445–1455.
Davies, L.C., Rosas, M., Jenkins, S.J., Liao, C.T., Scurr, M.J., Brombacher, F., Fraser, D.J., Allen, J.E., Jones, S.A., Taylor, P.R., Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat. Commun., 4, 2013, 1886.
de Heer, H.J., Hammad, H., Soullié, T., Hijdra, D., Vos, N., Willart, M.A., Hoogsteden, H.C., Lambrecht, B.N., Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200 (2004), 89–98.
Eder, W., Ege, M.J., von Mutius, E., The asthma epidemic. N. Engl. J. Med. 355 (2006), 2226–2235.
Eisenbarth, S.C., Piggott, D.A., Huleatt, J.W., Visintin, I., Herrick, C.A., Bottomly, K., Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med. 196 (2002), 1645–1651.
Epelman, S., Lavine, K.J., Beaudin, A.E., Sojka, D.K., Carrero, J.A., Calderon, B., Brija, T., Gautier, E.L., Ivanov, S., Satpathy, A.T., et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40 (2014), 91–104.
Gautier, E.L., Shay, T., Miller, J., Greter, M., Jakubzick, C., Ivanov, S., Helft, J., Chow, A., Elpek, K.G., Gordonov, S., et al., Immunological Genome Consortium. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13 (2012), 1118–1128.
Geissmann, F., Jung, S., Littman, D.R., Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19 (2003), 71–82.
Ginhoux, F., Guilliams, M., Tissue-Resident Macrophage Ontogeny and Homeostasis. Immunity 44 (2016), 439–449.
Gomez Perdiguero, E., Klapproth, K., Schulz, C., Busch, K., Azzoni, E., Crozet, L., Garner, H., Trouillet, C., de Bruijn, M.F., Geissmann, F., Rodewald, H.R., Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518 (2015), 547–551.
Häcker, H., Mischak, H., Häcker, G., Eser, S., Prenzel, N., Ullrich, A., Wagner, H., Cell type-specific activation of mitogen-activated protein kinases by CpG-DNA controls interleukin-12 release from antigen-presenting cells. EMBO J. 18 (1999), 6973–6982.
Hammad, H., Chieppa, M., Perros, F., Willart, M.A., Germain, R.N., Lambrecht, B.N., House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat. Med. 15 (2009), 410–416.
Hanna, R.N., Carlin, L.M., Hubbeling, H.G., Nackiewicz, D., Green, A.M., Punt, J.A., Geissmann, F., Hedrick, C.C., The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat. Immunol. 12 (2011), 778–785.
Hashimoto, D., Chow, A., Noizat, C., Teo, P., Beasley, M.B., Leboeuf, M., Becker, C.D., See, P., Price, J., Lucas, D., et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38 (2013), 792–804.
Hoppstädter, J., Diesel, B., Zarbock, R., Breinig, T., Monz, D., Koch, M., Meyerhans, A., Gortner, L., Lehr, C.M., Huwer, H., Kiemer, A.K., Differential cell reaction upon Toll-like receptor 4 and 9 activation in human alveolar and lung interstitial macrophages. Respir. Res., 11, 2010, 124.
Kline, J.N., Waldschmidt, T.J., Businga, T.R., Lemish, J.E., Weinstock, J.V., Thorne, P.S., Krieg, A.M., Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J. Immunol. 160 (1998), 2555–2559.
Kline, J.N., Kitagaki, K., Businga, T.R., Jain, V.V., Treatment of established asthma in a murine model using CpG oligodeoxynucleotides. Am. J. Physiol. Lung Cell. Mol. Physiol. 283 (2002), L170–L179.
Krieg, A.M., Therapeutic potential of Toll-like receptor 9 activation. Nat. Rev. Drug Discov. 5 (2006), 471–484.
Krieg, A.M., CpG still rocks! Update on an accidental drug. Nucleic Acid Ther. 22 (2012), 77–89.
Lambrecht, B.N., De Veerman, M., Coyle, A.J., Gutierrez-Ramos, J.C., Thielemans, K., Pauwels, R.A., Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Invest. 106 (2000), 551–559.
Lazarus, R., Klimecki, W.T., Raby, B.A., Vercelli, D., Palmer, L.J., Kwiatkowski, D.J., Silverman, E.K., Martinez, F., Weiss, S.T., Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies. Genomics 81 (2003), 85–91.
Marichal, T., Bedoret, D., Mesnil, C., Pichavant, M., Goriely, S., Trottein, F., Cataldo, D., Goldman, M., Lekeux, P., Bureau, F., Desmet, C.J., Interferon response factor 3 is essential for house dust mite-induced airway allergy. J. Allergy Clin. Immunol. 126 (2010), 836–844.e13.
Mesnil, C., Raulier, S., Paulissen, G., Xiao, X., Birrell, M.A., Pirottin, D., Janss, T., Starkl, P., Ramery, E., Henket, M., et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J. Clin. Invest. 126 (2016), 3279–3295.
Monsalve, E., Ruiz-García, A., Baladrón, V., Ruiz-Hidalgo, M.J., Sánchez-Solana, B., Rivero, S., García-Ramírez, J.J., Rubio, A., Laborda, J., Díaz-Guerra, M.J., Notch1 upregulates LPS-induced macrophage activation by increasing NF-kappaB activity. Eur. J. Immunol. 39 (2009), 2556–2570.
Mosser, D.M., Edwards, J.P., Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8 (2008), 958–969.
Ostuni, R., Piccolo, V., Barozzi, I., Polletti, S., Termanini, A., Bonifacio, S., Curina, A., Prosperini, E., Ghisletti, S., Natoli, G., Latent enhancers activated by stimulation in differentiated cells. Cell 152 (2013), 157–171.
Roy, S.R., Schiltz, A.M., Marotta, A., Shen, Y., Liu, A.H., Bacterial DNA in house and farm barn dust. J. Allergy Clin. Immunol. 112 (2003), 571–578.
Schuijs, M.J., Willart, M.A., Vergote, K., Gras, D., Deswarte, K., Ege, M.J., Madeira, F.B., Beyaert, R., van Loo, G., Bracher, F., et al. Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells. Science 349 (2015), 1106–1110.
Serbina, N.V., Pamer, E.G., Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7 (2006), 311–317.
Smit, L.A., Siroux, V., Bouzigon, E., Oryszczyn, M.P., Lathrop, M., Demenais, F., Kauffmann, F., Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA) Cooperative Group. CD14 and toll-like receptor gene polymorphisms, country living, and asthma in adults. Am. J. Respir. Crit. Care Med. 179 (2009), 363–368.
Strachan, D.P., Hay fever, hygiene, and household size. BMJ 299 (1989), 1259–1260.
Sur, S., Wild, J.S., Choudhury, B.K., Sur, N., Alam, R., Klinman, D.M., Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynucleotides. J. Immunol. 162 (1999), 6284–6293.
Swirski, F.K., Nahrendorf, M., Etzrodt, M., Wildgruber, M., Cortez-Retamozo, V., Panizzi, P., Figueiredo, J.L., Kohler, R.H., Chudnovskiy, A., Waterman, P., et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325 (2009), 612–616.
Tamoutounour, S., Guilliams, M., Montanana Sanchis, F., Liu, H., Terhorst, D., Malosse, C., Pollet, E., Ardouin, L., Luche, H., Sanchez, C., et al. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39 (2013), 925–938.
Tan, S.Y., Krasnow, M.A., Developmental origin of lung macrophage diversity. Development 143 (2016), 1318–1327.
Thorne, P.S., Kulhánková, K., Yin, M., Cohn, R., Arbes, S.J. Jr., Zeldin, D.C., Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing. Am. J. Respir. Crit. Care Med. 172 (2005), 1371–1377.
van Furth, R., Cohn, Z.A., The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 128 (1968), 415–435.
van Rijt, L.S., Jung, S., Kleinjan, A., Vos, N., Willart, M., Duez, C., Hoogsteden, H.C., Lambrecht, B.N., In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201 (2005), 981–991.
von Mutius, E., The microbial environment and its influence on asthma prevention in early life. J. Allergy Clin. Immunol. 137 (2016), 680–689.
