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NOD2 triggers an interleukin-32–dependent human dendritic cell program in leprosy

Nature Medicine volume 18, pages 555–563 (2012)Cite this article

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Abstract

It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony–stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I–restricted CD8+ T cells. Expression of NOD2 and IL-32 and the frequency of CD1b+ DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand–induced, IL-32–dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans.

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Figure 1: NOD2L and TLR2/1L induce functionally divergent DC-specific pathways.
Figure 2: NOD2L is a potent inducer of functional CD1b+ DCs.
Figure 3: NOD2L induces an IL-32–dependent DC program.
Figure 4: IL-32–induced DCs are potent antigen-presenting cells for MHC class I–restricted antigens.
Figure 5: IL-32 activates a DC program in leprosy.
Figure 6: Monocytes from patients with L-lep show reduced induction of CD1b+ DCs in response to NOD2L compared to healthy controls.

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References

  1. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C.A.J. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).

    Article  CAS  Google Scholar 

  2. Brightbill, H.D. et al. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285, 732–736 (1999).

    Article  CAS  Google Scholar 

  3. Ferwerda, G. et al. NOD2 and Toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog. 1, 279–285 (2005).

    Article  CAS  Google Scholar 

  4. Bloom, B.R. Learning from leprosy: A perspective on immunology and the third world. J. Immunol. 137, i–x (1986).

    CAS  PubMed  Google Scholar 

  5. Ridley, D.S. & Jopling, W.H. Classification of leprosy according to immunity. A five-group system. Int. J. Lepr. Other Mycobact. Dis. 34, 255–273 (1966).

    CAS  PubMed  Google Scholar 

  6. Yamamura, M. et al. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science 254, 277–279 (1991).

    Article  CAS  Google Scholar 

  7. Salgame, P. et al. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 254, 279–282 (1991).

    Article  CAS  Google Scholar 

  8. Sieling, P.A. et al. CD1 expression by dendritic cells in human leprosy lesions: Correlation with effective host immunity. J. Immunol. 162, 1851–1858 (1999).

    CAS  PubMed  Google Scholar 

  9. Takeuchi, O. et al. Role of TLR1 in mediating immune response to microbial lipoproteins. J. Immunol. 169, 10–14 (2002).

    Article  CAS  Google Scholar 

  10. Krutzik, S.R. et al. Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat. Med. 9, 525–532 (2003).

    Article  CAS  Google Scholar 

  11. Kang, T.J. & Chae, G.T. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol. Med. Microbiol. 31, 53–58 (2001).

    Article  CAS  Google Scholar 

  12. Kang, T.J., Lee, S.B. & Chae, G.T. A polymorphism in the Toll-like receptor 2 is associated with IL-12 production from monocyte in lepromatous leprosy. Cytokine 20, 56–62 (2002).

    Article  CAS  Google Scholar 

  13. Bochud, P.Y., Hawn, T.R. & Aderem, A. Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J. Immunol. 170, 3451–3454 (2003).

    Article  CAS  Google Scholar 

  14. Schröder, N.W. et al. High frequency of polymorphism Arg753Gln of the Toll-like receptor-2 gene detected by a novel allele-specific PCR. J. Mol. Med. 81, 368–372 (2003).

    Article  Google Scholar 

  15. Kang, T.J., Yeum, C.E., Kim, B.C., You, E.Y. & Chae, G.T. Differential production of interleukin-10 and interleukin-12 in mononuclear cells from leprosy patients with a Toll-like receptor 2 mutation. Immunology 112, 674–680 (2004).

    Article  CAS  Google Scholar 

  16. Malhotra, D., Relhan, V., Reddy, B.S. & Bamezai, R. TLR2 Arg677Trp polymorphism in leprosy: revisited. Hum. Genet. 116, 413–415 (2005).

    Article  CAS  Google Scholar 

  17. Johnson, C.M. et al. Cutting edge: A common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J. Immunol. 178, 7520–7524 (2007).

    Article  CAS  Google Scholar 

  18. Misch, E.A. et al. Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS Negl. Trop. Dis. 2, e231 (2008).

    Article  Google Scholar 

  19. Schuring, R.P. et al. Polymorphism N248S in the human Toll-like receptor 1 gene is related to leprosy and leprosy reactions. J. Infect. Dis. 199, 1816–1819 (2009).

    Article  CAS  Google Scholar 

  20. Yang, Y. et al. NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2. J. Biol. Chem. 282, 36223–36229 (2007).

    Article  CAS  Google Scholar 

  21. Girardin, S.E. et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. 278, 8869–8872 (2003).

    Article  CAS  Google Scholar 

  22. Zhang, F.R. et al. Genomewide association study of leprosy. N. Engl. J. Med. 361, 2609–2618 (2009).

    Article  CAS  Google Scholar 

  23. Berrington, W.R. et al. Common polymorphisms in the NOD2 gene region are associated with leprosy and its reactive states. J. Infect. Dis. 201, 1422–1435 (2010).

    Article  CAS  Google Scholar 

  24. Krutzik, S.R. et al. TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat. Med. 11, 653–660 (2005).

    Article  CAS  Google Scholar 

  25. Niazi, K.R. et al. Activation of human CD4+ T cells by targeting MHC class II epitopes to endosomal compartments using human CD1 tail sequences. Immunology 122, 522–531 (2007).

    Article  CAS  Google Scholar 

  26. Netea, M.G. et al. Interleukin-32 induces the differentiation of monocytes into macrophage-like cells. Proc. Natl. Acad. Sci. USA 105, 3515–3520 (2008).

    Article  CAS  Google Scholar 

  27. Netea, M.G. et al. Mycobacterium tuberculosis induces interleukin-32 production through a caspase-1/IL-18/interferon-γ–dependent mechanism. PLoS Med. 3, e277 (2006).

    Article  Google Scholar 

  28. Bai, X. et al. IL-32 is a host protective cytokine against Mycobacterium tuberculosis in differentiated THP-1 human macrophages. J. Immunol. 184, 3830–3840 (2010).

    Article  CAS  Google Scholar 

  29. Nold, M.F. et al. Endogenous IL-32 controls cytokine and HIV-1 production. J. Immunol. 181, 557–565 (2008).

    Article  CAS  Google Scholar 

  30. Li, W. et al. Activation of interleukin-32 pro-inflammatory pathway in response to influenza A virus infection. PLoS ONE 3, e1985 (2008).

    Article  Google Scholar 

  31. Joosten, L.A. et al. IL-32, a proinflammatory cytokine in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 103, 3298–3303 (2006).

    Article  CAS  Google Scholar 

  32. Shioya, M. et al. Epithelial overexpression of interleukin-32α in inflammatory bowel disease. Clin. Exp. Immunol. 149, 480–486 (2007).

    Article  CAS  Google Scholar 

  33. Marcondes, A.M. et al. Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function. Proc. Natl. Acad. Sci. USA 105, 2865–2870 (2008).

    Article  CAS  Google Scholar 

  34. Lee, D.J. et al. LILRA2 activation inhibits dendritic cell differentiation and antigen presentation to T cells. J. Immunol. 179, 8128–8136 (2007).

    Article  CAS  Google Scholar 

  35. Bleharski, J.R. et al. Use of genetic profiling in leprosy to discriminate clinical forms of the disease. Science 301, 1527–1530 (2003).

    Article  CAS  Google Scholar 

  36. Montoya, D. et al. Divergence of macrophage phagocytic and antimicrobial programs in leprosy. Cell Host Microbe 6, 343–353 (2009).

    Article  CAS  Google Scholar 

  37. Sieling, P.A. et al. CD1-restricted T cell recognition of microbial lipoglycans. Science 269, 227–230 (1995).

    Article  CAS  Google Scholar 

  38. Sieling, P.A. et al. Immunosuppressive roles for interleukin-10 and interleukin-4 in human infection: in vitro modulation of T cell responses in leprosy. J. Immunol. 150, 5501–5510 (1993).

    CAS  PubMed  Google Scholar 

  39. Krutzik, S.R. et al. IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D–dependent antimicrobial pathway. J. Immunol. 181, 7115–7120 (2008).

    Article  CAS  Google Scholar 

  40. Sallusto, F. & Lanzavecchia, A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony–stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor αa. J. Exp. Med. 179, 1109–1118 (1994).

    Article  CAS  Google Scholar 

  41. Silva, C.L., Palacios, A., Colston, M.J. & Lowrie, D.B. Mycobacterium leprae 65hsp antigen expressed from a retroviral vector in a macrophage cell line is presented to T cells in association with MHC class II in addition to MHC class I. Microb. Pathog. 12, 27–38 (1992).

    Article  CAS  Google Scholar 

  42. Modlin, R.L., Hofman, F.M., Taylor, C.R. & Rea, T.H. T lymphocyte subsets in the skin lesions of patients with leprosy. J. Am. Acad. Dermatol. 8, 182–189 (1983).

    Article  CAS  Google Scholar 

  43. Jung, M.Y., Son, M.H., Kim, S.H., Cho, D. & Kim, T.S. IL-32γ induces the maturation of dendritic cells with TH1- and TH17-polarizing ability through enhanced IL-12 and IL-6 production. J. Immunol. 186, 6848–6859 (2011).

    Article  CAS  Google Scholar 

  44. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).

    Article  CAS  Google Scholar 

  45. Coley, W.B. The treatment of malignant tumors by repeated inoculations of erysipelas: With a report of ten original cases. Am. J. Med. Sci. 105, 487–511 (1893).

    Article  Google Scholar 

  46. Morales, A., Eidinger, D. & Bruce, A.W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol. 116, 180–183 (1976).

    Article  CAS  Google Scholar 

  47. Morton, D., Eilber, F.R., Malmgren, R.A. & Wood, W.C. Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery 68, 158–163 (1970).

    CAS  PubMed  Google Scholar 

  48. Adam, A., Ciorbaru, R., Ellouz, F., Petit, J.F. & Lederer, E. Adjuvant activity of monomeric bacterial cell wall peptidoglycans. Biochem. Biophys. Res. Commun. 56, 561–567 (1974).

    Article  CAS  Google Scholar 

  49. Ellouz, F., Adam, A., Ciorbaru, R. & Lederer, E. Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem. Biophys. Res. Commun. 59, 1317–1325 (1974).

    Article  CAS  Google Scholar 

  50. Specter, S., Cimprich, R., Friedman, H. & Chedid, L. Stimulation of an enhanced in vitro immune response by a synthetic adjuvant, muramyl dipeptide. J. Immunol. 120, 487–491 (1978).

    CAS  PubMed  Google Scholar 

  51. Sugimoto, M., Germain, R.N., Chedid, L. & Benacerraf, B. Enhancement of carrier-specific helper T cell function by the synthetic adjuvant, N-acetyl muramyl-L-alanyl-D-isoglutamine (MDP). J. Immunol. 120, 980–982 (1978).

    CAS  PubMed  Google Scholar 

  52. Kleinerman, E.S. et al. Unique histological changes in lung metastases of osteosarcoma patients following therapy with liposomal muramyl tripeptide (CGP 19835A lipid). Cancer Immunol. Immunother. 34, 211–220 (1992).

    Article  CAS  Google Scholar 

  53. Ridley, D.S. Histological classification and the immunological spectrum of leprosy. Bull. World Health Organ. 51, 451–465 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Liu, P.T. et al. Toll-like receptor triggering of a vitamin D–mediated human antimicrobial response. Science 311, 1770–1773 (2006).

    Article  CAS  Google Scholar 

  55. Monney, L. et al. TH1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536–541 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank P. Liu, B. Bloom and F. Martinon for helpful scientific discussions, D. Vu for technical assistance and A. De Leon for help with the immunolabeling. This work was supported in parts by grants from the US National Institutes of Health (R01s AI022553, AR040312 and AI047868) and the Swiss National Science Foundation (SSMBS, PASMP3-123256).

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Author notes

  1. Delphine J Lee

    Present address: Present address: Department of Translational Immunology, John Wayne Cancer Institute, Santa Monica, California, USA.,

Authors and Affiliations

  1. Department of Medicine, Division of Dermatology, David Geffen School of Medicine at University of California–Los Angeles (UCLA), Los Angeles, California, USA

    Mirjam Schenk, Stephan R Krutzik, Peter A Sieling, Delphine J Lee, Rosane M B Teles, Maria Teresa Ochoa & Robert L Modlin

  2. Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, Institute for Molecular Medicine, Jonsson Comprehensive Cancer Center and California NanoSystems Institute, David Geffen School of Medicine, University of California, Los Angeles, California, USA

    Evangelia Komisopoulou & Thomas G Graeber

  3. Department of Mycobacteriosis, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil

    Euzenir N Sarno

  4. Department of Dermatology, University of Southern California School of Medicine, Los Angeles, California, USA

    Thomas H Rea

  5. Department of Biomedical Science and Technology, Konkuk University, Seoul, Korea

    Soohyun Kim

  6. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA

    Genhong Cheng & Robert L Modlin

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Contributions

R.L.M. and M.S. designed the experiments, interpreted the data and did the majority of the writing. M.S., S.R.K. and P.A.S. performed the experiments. D.J.L. helped with functional microarray analysis. R.M.B.T. provided the leprosy microarray data. M.T.O. performed the confocal imaging. E.K. and T.G.G. performed the bioinformatics analysis. E.N.S. and T.H.R. provided the clinical samples and helped interpret data. S.K. provided reagents and expertise on IL-32. G.C. helped with the conceptual framework and direction of the study.

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Correspondence to Robert L Modlin.

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Schenk, M., Krutzik, S., Sieling, P. et al. NOD2 triggers an interleukin-32–dependent human dendritic cell program in leprosy. Nat Med 18, 555–563 (2012). https://doi.org/10.1038/nm.2650

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