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Cholesterol depletion associated with Leishmania major infection alters macrophage CD40 signalosome composition and effector function

Nature Immunology volume 10, pages 273–280 (2009)Cite this article

A Corrigendum to this article was published on 01 June 2009

This article has been updated

Abstract

CD40, a costimulatory molecule expressed on macrophages, induces expression of interleukin 12 (IL-12) in uninfected macrophages and IL-10 in macrophages infected with Leishmania major. IL-12 suppresses, whereas IL-10 enhances, L. major infection. The mechanisms that regulate this difference in CD40-induced cytokine production remain unclear, but it is known that L. major depletes cholesterol. Here we show that cholesterol influenced the assembly of distinct CD40 signalosomes. Depletion of membrane cholesterol inhibited the assembly of an IL-12-inducing CD40 signalosome containing the adaptors TRAF2, TRAF3 and TRAF5 and the kinase Lyn and promoted the assembly of an IL-10-inducing CD40 signalosome containing the adaptor TRAF6 and the kinase Syk. Thus, cholesterol depletion might represent an immune-evasion strategy used by L. major.

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Figure 1: Cholesterol depletion impairs CD40-induced phosphorylation of p38 and its associated effector functions but augments Erk1/2 phosphorylation and its associated effector functions in uninfected and L. major–infected macrophages.
Figure 2: CD40-induced phosphorylation of p38 and Erk1/2 is modulated by membrane localization, cholesterol and L. major infection.
Figure 3: TRAF proteins associate with CD40 in different ways in detergent-resistant and detergent-soluble fractions.
Figure 4: Cholesterol influences anti-leishmanial functions.
Figure 5: Loss of the protective influence of mevalonate in CD40-deficient mice.
Figure 6: TRAF6 expression suppresses anti-leishmanial immunity.

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  • 18 May 2009

    NOTE: In the version of this article initially published, the GenBank accession number for the Indian human immunodeficiency virus 2 isolate is incorrect. The correct accession number is DQ307022. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

Anti-CD40 was from G. Klaus (National Institute of Medical Research). Supported by the Department of Biotechnology, New Delhi; the Government of India; Centre Franco-Indien pour la Promotion de la Recherche Avancée, New Delhi; and the Council of Scientific and Industrial Research, New Delhi (A.R.).

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Authors and Affiliations

  1. National Centre for Cell Science, Ganeshkhind, Pune, 411007, India

    Abdur Rub, Ranadhir Dey, Meenakshi Jadhav & Bhaskar Saha

  2. Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, 410210, India

    Rohan Kamat, Santhosh Chakkaramakkil & Robin Mukhopadhyaya

  3. Bose Institute, Calcutta Improvement Trust Scheme, Kolkata, 7000054, India

    Subrata Majumdar

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A.R. and R.D., all fractionation studies; A.R. and M.J., in vivo experiments; R.K. and S.C., shRNA vector and virus preparation; and S.M., R.M. and B.S., manuscript preparation.

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Correspondence to Bhaskar Saha.

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Rub, A., Dey, R., Jadhav, M. et al. Cholesterol depletion associated with Leishmania major infection alters macrophage CD40 signalosome composition and effector function. Nat Immunol 10, 273–280 (2009). https://doi.org/10.1038/ni.1705

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