[en] Sirtuins are a unique class of NAD+-dependent deacetylases that regulate diverse biological functions such as aging, metabolism, and stress resistance. Recently, it has been shown that sirtuins may have anti-inflammatory activities by inhibiting proinflammatory transcription factors such as NF-κB. In contrast, we report in this study that pharmacological inhibition of sirtuins dampens adaptive Th2 responses and subsequent allergic inflammation by interfering with lung dendritic cell (DC) function in a mouse model of airway allergy. Using genetic engineering, we demonstrate that sirtuin 1 represses the activity of the nuclear receptor peroxisome proliferator-activated receptor-γ in DCs, thereby favoring their maturation toward a pro-Th2 phenotype. This study reveals a previously unappreciated function of sirtuin 1 in the regulation of DC function and Th2 responses, thus shedding new light on our current knowledge on the regulation of inflammatory processes by sirtuins.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Legutko, Agnieszka ✱; Université de Liège - ULiège > Laboratory of Cellular and Molecular Physiology, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-Research)
Marichal, Thomas ✱; Université de Liège - ULiège > Laboratory of Cellular and Molecular Physiology, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-Research)
Fievez, Laurence ; Université de Liège - ULiège > Département de sciences fonctionnelles > GIGA-R : Biochimie et biologie moléculaire
Bedoret, Denis; Université de Liège - ULiège > Laboratory of Cellular and Molecular Physiology, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-Research)
Mayer, Alice; Université de Liège - ULiège > Faculty of Veterinary Medicine
de Vries, Hilda; Université Libre de Bruxelles - ULB > Laboratory of Animal Physiology, Institute of Molecular Biology and Medicine
Klotz, Luisa; The Netherlands Cancer Institute, Amsterdam, The Netherlands
Drion, Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R:Méth. expér.des anim. de labo et éth. en expér. anim.
Heirman, Carlo; Université de Liège - ULiège > Animal Facility, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-Research)
CATALDO, Didier ; Centre Hospitalier Universitaire de Liège - CHU > Pneumologie-Allergologie
LOUIS, Renaud ; Centre Hospitalier Universitaire de Liège - CHU > Pneumologie-Allergologie
Thielemans, Kris
Andris, Fabienne; Université Libre de Bruxelles - ULB > Department of Physiology and Immunology
Leo, Oberdan
Lekeux, Pierre ; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
Desmet, Christophe ✱; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
Bureau, Fabrice ✱; Université de Liège - ULiège > Département de sciences fonctionnelles > GIGA-R : Biochimie et biologie moléculaire
Zhu, J., and W. E. Paul. 2008. CD4 T cells: fates, functions, and faults. Blood 112: 1557-1569.
Lloyd, C. M., and E. M. Hessel. 2010. Functions of T cells in asthma: more than just T(H)2 cells. Nat. Rev. Immunol. 10: 838-848.
Paul, W. E., and J. Zhu. 2010. How are T(H)2-type immune responses initiated and amplified? Nat. Rev. Immunol. 10: 225-235.
Banchereau, J., F. Briere, C. Caux, J. Davoust, S. Lebecque, Y. J. Liu, B. Pulendran, and K. Palucka. 2000. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18: 767-811. (Pubitemid 30365397)
Masoli, M., D. Fabian, S. Holt, R. Beasley; Global Initiative for Asthma (GINA) Program. 2004. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59: 469-478. (Pubitemid 38580764)
Barnes, P. J. 2008. Immunology of asthma and chronic obstructive pulmonary disease. Nat. Rev. Immunol. 8: 183-192. (Pubitemid 351323287)
Sauve, A. A., C. Wolberger, V. L. Schramm, and J. D. Boeke. 2006. The biochemistry of sirtuins. Annu. Rev. Biochem. 75: 435-465. (Pubitemid 44118039)
Michan, S., and D. Sinclair. 2007. Sirtuins in mammals: insights into their biological function. Biochem. J. 404: 1-13. (Pubitemid 46788079)
Finkel, T., C.-X. Deng, and R. Mostoslavsky. 2009. Recent progress in the biology and physiology of sirtuins. Nature 460: 587-591.
Haigis, M. C., and L. P. Guarente. 2006. Mammalian sirtuins - emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20: 2913-2921. (Pubitemid 44771725)
Saunders, L. R., and E. Verdin. 2007. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 26: 5489-5504. (Pubitemid 47255930)
Yamamoto, H., K. Schoonjans, and J. Auwerx. 2007. Sirtuin functions in health and disease. Mol. Endocrinol. 21: 1745-1755. (Pubitemid 47173788)
Gan, L., and L. Mucke. 2008. Paths of convergence: sirtuins in aging and neurodegeneration. Neuron 58: 10-14. (Pubitemid 351467036)
Yeung, F., J. E. Hoberg, C. S. Ramsey, M. D. Keller, D. R. Jones, R. A. Frye, and M. W. Mayo. 2004. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23: 2369-2380. (Pubitemid 38954844)
Yang, S.-R., J. Wright, M. Bauter, K. Seweryniak, A. Kode, and I. Rahman. 2007. Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-κB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging. Am. J. Physiol. Lung Cell. Mol. Physiol. 292: L567-L576.
Gao, Z., and J. Ye. 2008. Inhibition of transcriptional activity of c-JUN by SIRT1. Biochem. Biophys. Res. Commun. 376: 793-796.
Rajendrasozhan, S., S.-R. Yang, V. L. Kinnula, and I. Rahman. 2008. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 177: 861-870. (Pubitemid 351600664)
Yoshizaki, T., J. C. Milne, T. Imamura, S. Schenk, N. Sonoda, J. L. Babendure, J.-C. Lu, J. J. Smith, M. R. Jirousek, and J. M. Olefsky. 2009. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol. Cell. Biol. 29: 1363-1374.
Pfluger, P. T., D. Herranz, S. Velasco-Miguel, M. Serrano, and M. H. Tschöp. 2008. Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl. Acad. Sci. USA 105: 9793-9798. (Pubitemid 352031379)
Purushotham, A., T. T. Schug, Q. Xu, S. Surapureddi, X. Guo, and X. Li. 2009. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 9: 327-338.
Schug, T. T., Q. Xu, H. Gao, A. Peres-da-Silva, D. W. Draper, M. B. Fessler, A. Purushotham, and X. Li. 2010. Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol. Cell. Biol. 30: 4712-4721.
Xu, F., Z. Gao, J. Zhang, C. A. Rivera, J. Yin, J. Weng, and J. Ye. 2010. Lack of SIRT1 (Mammalian Sirtuin 1) activity leads to liver steatosis in the SIRT1+/- mice: a role of lipid mobilization and inflammation. Endocrinology 151: 2504-2514.
Yoshizaki, T., S. Schenk, T. Imamura, J. L. Babendure, N. Sonoda, E. J. Bae, D. Y. Oh, M. Lu, J. C. Milne, C. Westphal, et al. 2010. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 298: E419-E428.
Kawahara, T. L. A., E. Michishita, A. S. Adler, M. Damian, E. Berber, M. Lin, R. A. McCord, K. C. L. Ongaigui, L. D. Boxer, H. Y. Chang, and K. F. Chua. 2009. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136: 62-74.
Van Gool, F., M. Gallí, C. Gueydan, V. Kruys, P.-P. Prevot, A. Bedalov, R. Mostoslavsky, F. W. Alt, T. De Smedt, and O. Leo. 2009. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat. Med. 15: 206-210.
Grozinger, C. M., E. D. Chao, H. E. Blackwell, D. Moazed, and S. L. Schreiber. 2001. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J. Biol. Chem. 276: 38837-38843.
Mai, A., S. Massa, S. Lavu, R. Pezzi, S. Simeoni, R. Ragno, F. R. Mariotti, F. Chiani, G. Camilloni, and D. A. Sinclair. 2005. Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. J. Med. Chem. 48: 7789-7795. (Pubitemid 41698818)
Kim, S. R., K. S. Lee, S. J. Park, K. H. Min, Y. H. Choe, H. Moon, W. H. Yoo, H. J. Chae, M. K. Han, and Y. C. Lee. 2010. Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease. J. Allergy Clin. Immunol. 125: 449-460, e14.
Heltweg, B., T. Gatbonton, A. D. Schuler, J. Posakony, H. Li, S. Goehle, R. Kollipara, R. A. Depinho, Y. Gu, J. A. Simon, and A. Bedalov. 2006. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66: 4368-4377.
Gueders, M. M., P. Bertholet, F. Perin, N. Rocks, R. Maree, V. Botta, R. Louis, J.-M. Foidart, A. Noel, B. Evrard, and D. D. Cataldo. 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. (Pubitemid 350298479)
Bedoret, D., H.Wallemacq, T. Marichal, C. Desmet, F. Quesada Calvo, E. Henry, R. Closset, B. Dewals, C. Thielen, P. Gustin, et al. 2009. Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice. J. Clin. Invest. 119: 3723-3738.
Inaba, K., M. Pack, M. Inaba, H. Sakuta, F. Isdell, and R. M. Steinman. 1997. High levels of a major histocompatibility complex II-self peptide complex on dendritic cells from the T cell areas of lymph nodes. J. Exp. Med. 186: 665-672. (Pubitemid 27381531)
Bureau, F., G. Bonizzi, N. Kirschvink, S. Delhalle, D. Desmecht, M.-P. Merville, V. Bours, and P. Lekeux. 2000. Correlation between nuclear factor-kappaB activity in bronchial brushing samples and lung dysfunction in an animal model of asthma. Am. J. Respir. Crit. Care Med. 161: 1314-1321. (Pubitemid 30243847)
Schachtrup, C., T. Emmler, B. Bleck, A. Sandqvist, and F. Spener. 2004. Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins. Biochem. J. 382: 239-245. (Pubitemid 39141587)
Tiscornia, G., O. Singer, and I. M. Verma. 2006. Production and purification of lentiviral vectors. Nat. Protoc. 1: 241-245.
Henry, E., C. J. Desmet, V. Garzé, L. Fiévez, D. Bedoret, C. Heirman, P. Faisca, F. J. Jaspar, P. Gosset, A. P. A. Jacquet, et al. 2008. Dendritic cells genetically engineered to express IL-10 induce long-lasting antigen-specific tolerance in experimental asthma. J. Immunol. 181: 7230-7242.
van Rijt, L. S., S. Jung, A. Kleinjan, N. Vos, M. Willart, C. Duez, H. C. Hoogsteden, and B. N. Lambrecht. 2005. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201: 981-991.
Vermaelen, K. Y., I. Carro-Muino, B. N. Lambrecht, and R. A. Pauwels. 2001. Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes. J. Exp. Med. 193: 51-60. (Pubitemid 32060697)
Lambrecht, B. N., M. De Veerman, A. J. Coyle, J. C. Gutierrez-Ramos, K. Thielemans, and R. A. Pauwels. 2000. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Invest. 106: 551-559. (Pubitemid 30666388)
Saeki, H., A. M. Moore, M. J. Brown, and S. T. Hwang. 1999. Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J. Immunol. 162: 2472-2475. (Pubitemid 29309263)
Murphy, K. M., A. B. Heimberger, and D. Y. Loh. 1990. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250: 1720-1723. (Pubitemid 120031881)
Raymond, M., M. Rubio, G. Fortin, K. H. Shalaby, H. Hammad, B. N. Lambrecht, and M. Sarfati. 2009. Selective control of SIRP-alpha-positive airway dendritic cell trafficking through CD47 is critical for the development of T(H)2-mediated allergic inflammation. J. Allergy Clin. Immunol. 124: 1333-1342, e1.
Picard, F., M. Kurtev, N. Chung, A. Topark-Ngarm, T. Senawong, R. Machado De Oliveira, M. Leid, M. W. McBurney, and L. Guarente. 2004. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429: 771-776. (Pubitemid 38833129)
Wang, F., and Q. Tong. 2009. SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1's repressive interaction with PPARgamma. Mol. Biol. Cell 20: 801-808.
Semple, R. K., V. K. Chatterjee, and S. O'Rahilly. 2006. PPAR g and human metabolic disease. J. Clin. Invest. 116: 581-589.
Hammad, H., H. J. de Heer, T. Soullié, V. Angeli, F. Trottein, H. C. Hoogsteden, and B. N. Lambrecht. 2004. Activation of peroxisome proliferator-activated receptor-g in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma. Am. J. Pathol. 164: 263-271. (Pubitemid 38364610)
He, W., Y. Barak, A. Hevener, P. Olson, D. Liao, J. Le, M. Nelson, E. Ong, J. M. Olefsky, and R. M. Evans. 2003. Adipose-specific peroxisome proliferator-activated receptor-γ knockout causes insulin resistance in fat and liver but not in muscle. Proc. Natl. Acad. Sci. USA 100: 15712-15717. (Pubitemid 38021055)
Cheng, H.-L., R. Mostoslavsky, S. i. Saito, J. P. Manis, Y. Gu, P. Patel, R. Bronson, E. Appella, F. W. Alt, and K. F. Chua. 2003. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl. Acad. Sci. USA 100: 10794-10799. (Pubitemid 37140107)
McBurney, M. W., X. Yang, K. Jardine, M. Hixon, K. Boekelheide, J. R. Webb, P. M. Lansdorp, and M. Lemieux. 2003. The mammalian SIR2α protein has a role in embryogenesis and gametogenesis. Mol. Cell. Biol. 23: 38-54. (Pubitemid 36008499)
Li, X., S. Zhang, G. Blander, J. G. Tse, M. Krieger, and L. Guarente. 2007. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol. Cell 28: 91-106. (Pubitemid 47531974)
Caton, M. L., M. R. Smith-Raska, and B. Reizis. 2007. Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen. J. Exp. Med. 204: 1653-1664. (Pubitemid 47048031)
Desmet, C., P. Gosset, B. Pajak, D. Cataldo, M. Bentires-Alj, P. Lekeux, and F. Bureau. 2004. Selective blockade of NF-κ B activity in airway immune cells inhibits the effector phase of experimental asthma. J. Immunol. 173: 5766-5775. (Pubitemid 39392166)
Desmet, C., P. Gosset, E. Henry, V. Garzé, P. Faisca, N. Vos, F. Jaspar, D. Mélotte, B. N. Lambrecht, D. Desmecht, et al. 2005. Treatment of experimental asthma by decoy-mediated local inhibition of activator protein-1. Am. J. Respir. Crit. Care Med. 172: 671-678. (Pubitemid 41324220)
Eltzschig, H. K., and P. Carmeliet. 2011. Hypoxia and inflammation. N. Engl. J. Med. 364: 656-665.
Stumbles, P. A., J. A. Thomas, C. L. Pimm, P. T. Lee, T. J. Venaille, S. Proksch, and P. G. Holt. 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. (Pubitemid 28562519)
Honda, K., P. Marquillies, M. Capron, and D. Dombrowicz. 2004. Peroxisome proliferator-activated receptor γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model. J. Allergy Clin. Immunol. 113: 882-888. (Pubitemid 38608597)
Mueller, C., V. Weaver, J. P. Vanden Heuvel, A. August, and M. T. Cantorna. 2003. Peroxisome proliferator-activated receptor g ligands attenuate immunological symptoms of experimental allergic asthma. Arch. Biochem. Biophys. 418: 186-196. (Pubitemid 37159385)
Trifilieff, A., A. Bench, M. Hanley, D. Bayley, E. Campbell, and P. Whittaker. 2003. PPAR-α and -gγbut not -δ agonists inhibit airway inflammation in a murine model of asthma: in vitro evidence for an NF-kappaB-independent effect. Br. J. Pharmacol. 139: 163-171. (Pubitemid 36645320)
Woerly, G., K. Honda, M. Loyens, J.-P. Papin, J. Auwerx, B. Staels, M. Capron, and D. Dombrowicz. 2003. Peroxisome proliferator-activated receptors α and γ down-regulate allergic inflammation and eosinophil activation. J. Exp. Med. 198: 411-421. (Pubitemid 36976052)
Ward, J. E., D. J. Fernandes, C. C. Taylor, J. V. Bonacci, L. Quan, and A. G. Stewart. 2006. The PPARgamma ligand, rosiglitazone, reduces airways hyperresponsiveness in a murine model of allergen-induced inflammation. Pulm. Pharmacol. Ther. 19: 39-46. (Pubitemid 41606851)
Ito, K., and P. J. Barnes. 2009. COPD as a disease of accelerated lung aging. Chest 135: 173-180.
Brunet, A., L. B. Sweeney, J. F. Sturgill, K. F. Chua, P. L. Greer, Y. Lin, H. Tran, S. E. Ross, R. Mostoslavsky, H. Y. Cohen, et al. 2004. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303: 2011-2015. (Pubitemid 38393275)
Motta, M. C., N. Divecha, M. Lemieux, C. Kamel, D. Chen, W. Gu, Y. Bultsma, M. McBurney, and L. Guarente. 2004. Mammalian SIRT1 represses forkhead transcription factors. Cell 116: 551-563. (Pubitemid 38264432)
Westerheide, S. D., J. Anckar, S. M. Stevens, Jr., L. Sistonen, and R. I. Morimoto. 2009. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323: 1063-1066.
Luo, J., A. Y. Nikolaev, S.-i. Imai, D. Chen, F. Su, A. Shiloh, L. Guarente, and W. Gu. 2001. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107: 137-148. (Pubitemid 33035941)
Vaziri, H., S. K. Dessain, E. Ng Eaton, S.-I. Imai, R. A. Frye, T. K. Pandita, L. Guarente, and R. A. Weinberg. 2001. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107: 149-159. (Pubitemid 33035942)
Idzko, M., H. Hammad, M. van Nimwegen, M. Kool, T. Müller, T. Soullié, M. A. M. Willart, D. Hijdra, H. C. Hoogsteden, and B. N. Lambrecht. 2006. Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J. Clin. Invest. 116: 2935-2944. (Pubitemid 44684478)
Idzko, M., H. Hammad, M. van Nimwegen, M. Kool, N. Vos, H. C. Hoogsteden, and B. N. Lambrecht. 2007. Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function. J. Clin. Invest. 117: 464-472. (Pubitemid 46203975)