Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

作者：Tan, Hong Yien; Yong, Yean Kong; Shankar, Esaki M.; Paukovics, Geza; Ellegard, Rada; Larsson, Marie; Kamarulzaman, Adeeba; French, Martyn A.^*; Crowe, Suzanne M.^*

来源：The Journal of Immunology, 2016, 196(10): 4052-4063.

DOI：10.4049/jimmunol.1502203

• HIV-INFECTED PATIENTS
• STARTING ANTIRETROVIRAL THERAPY
• CD4(+) T-CELLS
• MYCOBACTERIUM-TUBERCULOSIS
• HIV-1-INFECTED PATIENTS
• NLRP3 INFLAMMASOME
• RESTORATION DISEASE
• NITRIC-OXIDE
• COLLABORATIVE ANALYSIS
• INTERLEUKIN-18

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-1 beta, 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-18R alpha 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.

• 出版日期2016-5-15
• 单位河北医科大学