Aberrant inflammasome activation characterizes tuberculosis-associated immune reconstitution inflammatory syndrome

H.Y. Tan, Y.K. Yong, E.M. Shankar, G. Paukovics, R. Ellegard, M. Larsson, A. Kamarulzaman, Martyn French, S.M. Crowe

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    Abstract

    Copyright © 2016 by The American Association of Immunologists, Inc.Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre-and post-cART in TBIRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64+ monocytes were a marker of increased casp1 expression. Furthermore, IL-1β, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre-and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18Rα on CD4+ T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.
    Original languageEnglish
    Pages (from-to)4052-4063
    JournalJournal of Immunology
    Volume196
    Issue number10
    Early online date13 Apr 2016
    DOIs
    Publication statusPublished - 15 May 2016

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    Tan, H. Y., Yong, Y. K., Shankar, E. M., Paukovics, G., Ellegard, R., Larsson, M., ... Crowe, S. M. (2016). Aberrant inflammasome activation characterizes tuberculosis-associated immune reconstitution inflammatory syndrome. Journal of Immunology, 196(10), 4052-4063. https://doi.org/10.4049/jimmunol.1502203