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Activation and regulation of Toll-like receptors 2 and 1 in human leprosy

Nature Medicine volume 9, pages 525–532 (2003)Cite this article

Abstract

The expression and activation of Toll-like receptors (TLRs) was investigated in leprosy, a spectral disease in which clinical manifestations correlate with the type of immune response mounted toward Mycobacterium leprae. TLR2-TLR1 heterodimers mediated cell activation by killed M. leprae, indicating the presence of triacylated lipoproteins. A genome-wide scan of M. leprae detected 31 putative lipoproteins. Synthetic lipopeptides representing the 19-kD and 33-kD lipoproteins activated both monocytes and dendritic cells. Activation was enhanced by type-1 cytokines and inhibited by type-2 cytokines. In addition, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced TLR1 expression in monocytes and dendritic cells, respectively, whereas IL-4 downregulated TLR2 expression. TLR2 and TLR1 were more strongly expressed in lesions from the localized tuberculoid form (T-lep) as compared with the disseminated lepromatous form (L-lep) of the disease. These data provide evidence that regulated expression and activation of TLRs at the site of disease contribute to the host defense against microbial pathogens.

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Figure 1: TLR2 and TLR2-TLR1 mediate the response to M. leprae and M. leprae 19-kD and 33-kD lipopeptides.
Figure 2: Cytokine profiles influence TLR2-TLR1 activation of monocyte and monocyte-derived dendritic cells.
Figure 3: Effect of cytokines on TLR2 and TLR1 expression on monocytes and monocyte-derived dendritic cells.
Figure 4: TLR2 and TLR1 expression on peripheral monocytes, and activation of monocytes and monocyte-derived dendritic cells in leprosy patients.
Figure 5: Expression of TLR2 and TLR1 in leprosy patients.
Figure 6: Phenotype of cells expressing TLR2 in T-lep lesions.

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Acknowledgements

We thank D. Williams and T. Gillis (National Hansen's Disease Programs) for use of their unpublished data on expression of ML1966 mRNA, W. Chung for technical assistance and S. Smale for critical comments on the manuscript and scientific discussion. This work was supported in part by grants from the National Institutes of Health (AI07126, AI22553 and AI47866) and the World Health Organization (IMMLEP).

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Authors and Affiliations

  1. Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA

    Stephan R. Krutzik, Maria Teresa Ochoa, Peter A. Sieling, Yolanda W. Ng, Annaliza Legaspi, Philip T. Liu & Robert L. Modlin

  2. Department of Microbiology and Immunology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA

    Stephan R. Krutzik, Philip T. Liu & Robert L. Modlin

  3. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan Science and Technology Corporation, Osaka, Japan

    Satoshi Uematsu & Shizuo Akira

  4. Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, Paris, France

    Stewart T. Cole

  5. Department of Molecular Biology, Genentech Inc., South San Francisco, California, USA

    Paul J. Godowski

  6. Department of Microbiology, Leprosy Research Center, National Institute of Infectious Diseases, Higashimurayama, Tokyo, Japan

    Yumi Maeda

  7. Leprosy Laboratory Institute Oswaldo Cruz, Rio de Janeiro, Brazil

    Euzenir N. Sarno

  8. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Michael V. Norgard

  9. Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA

    Yumi Maeda & Patrick J. Brennan

  10. Section of Dermatology, University of Southern California School of Medicine, Los Angeles, California, USA

    Thomas H. Rea

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Correspondence to Robert L. Modlin.

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Krutzik, S., Ochoa, M., Sieling, P. et al. Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat Med 9, 525–532 (2003). https://doi.org/10.1038/nm864

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