Publications & Reports

Aberrant inflammasome activation characterizes tuberculosis-associated immune reconstitution inflammatory syndrome.

Tan HY, Yong YK, Shankar EM, Paukovics G, Ellegård R, Larsson M, Kamarulzaman A, French MA, Crowe SM
Centre of Excellence for Research in AIDS, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia;

Abstract

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 TB-IRIS 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-1beta, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation ofNLRP3andAIM2inflammasome 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-18Ralpha 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.

Link to publisher’s web site

Publication

  • Journal: Journal of Immunology
  • Published: 13/04/2016
  • Volume: 196
  • Issue: 10
  • Pagination: 4052-4063

Author

Health Issue