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Classical complement and inflammasome activation converge in CD14highCD16- monocytes in HIV associated TB-immune reconstitution inflammatory syndrome.

ABSTRACT: Inflammasome-derived cytokines, IL-1β and IL-18, and complement cascade have been independently implicated in the pathogenesis of tuberculosis (TB)-immune reconstitution inflammatory syndrome (TB-IRIS), a complication affecting HIV+ individuals starting antiretroviral therapy (ART). Although sublytic deposition of the membrane attack complex (MAC) has been shown to promote NLRP3 inflammasome activation, it is unknown whether these pathways may cooperatively contribute to TB-IRIS. To evaluate the activation of inflammasome, peripheral blood mononuclear cells (PBMCs) from HIV-TB co-infected patients prior to ART and at the IRIS or equivalent timepoint were incubated with a probe used to assess active caspase-1/4/5 followed by screening of ASC (apoptosis-associated speck-like protein containing a CARD domain) specks as a readout of inflammasome activation by imaging flow cytometry. We found higher numbers of monocytes showing spontaneous caspase-1/4/5+ASC-speck formation in TB-IRIS compared to TB non-IRIS patients. Moreover, numbers of caspase-1/4/5+ASC-speck+ monocytes positively correlated with IL-1β/IL-18 plasma levels. Besides increased systemic levels of C1q and C5a, TB-IRIS patients also showed elevated C1q and C3 deposition on monocyte cell surface, suggesting aberrant classical complement activation. A clustering tSNE analysis revealed TB-IRIS patients are enriched in a CD14highCD16- monocyte population that undergoes MAC deposition and caspase-1/4/5 activation compared to TB non-IRIS patients, suggesting complement-associated inflammasome activation during IRIS events. Accordingly, PBMCs from patients were more sensitive to ex-vivo complement-mediated IL-1β secretion than healthy control cells in a NLRP3-dependent manner. Therefore, our data suggest complement-associated inflammasome activation may fuel the dysregulated TB-IRIS systemic inflammatory cascade and targeting this pathway may represent a novel therapeutic approach for IRIS or related inflammatory syndromes.

SUBMITTER: Lage SL

PROVIDER: S-EPMC8041190 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwide. In some TB-HIV co-infected individuals treated for both diseases simultaneously, a pathological inflammatory reaction termed immune reconstitution inflammatory syndrome (IRIS) may occur. The risk factors for IRIS are not fully defined. We investigated the association of HLA-B, HLA-C, and KIR genotypes with TB, HIV-1 infection, and IRIS onset. METHODS:Patients were divided into four groups: Group 1- TB+/HIV+ (n?=?88; 11 of them with IRIS), Group 2- HIV+ (n?=?24), Group 3- TB+ (n?=?24) and Group 4- healthy volunteers (n?=?26). Patients were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. The HLA-B and HLA-C loci were typed using SBT, NGS, and KIR genes by PCR-SSP. Unconditional logistic regression models were performed for Protection/risk estimation. RESULTS:Among the individuals with TB as the outcome, KIR2DS2 was associated with increased risk for TB onset (aOR?=?2.39, P?=?0.04), whereas HLA-B*08 and female gender were associated with protection against TB onset (aOR?=?0.23, P?=?0.03, and aOR?=?0.33, P?=?0.01, respectively). Not carrying KIR2DL3 (aOR?=?0.18, P?=?0.03) and carrying HLA-C*07 (aOR?=?0.32, P?=?0.04) were associated with protection against TB onset among HIV-infected patients. An increased risk for IRIS onset was associated with having a CD8 count ?500 cells/mm3 (aOR?=?18.23, P?=?0.016); carrying the KIR2DS2 gene (aOR?=?27.22, P?=?0.032), the HLA-B*41 allele (aOR?=?68.84, P?=?0.033), the KIR2DS1?+?HLA-C2 pair (aOR?=?28.58, P?=?0.024); and not carrying the KIR2DL3?+?HLA-C1/C2 pair (aOR?=?43.04, P?=?0.034), and the KIR2DL1?+?HLA-C1/C2 pair (aOR?=?43.04, P?=?0.034), CONCLUSIONS: These results suggest the participation of these genes in the immunopathogenic mechanisms related to the conditions studied. This is the first study demonstrating an association of HLA-B*41, KIR2DS2, and KIR + HLA-C pairs with IRIS onset among TB-HIV co-infected individuals.

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Classical complement and inflammasome activation converge in CD14highCD16- monocytes in HIV associated TB-immune reconstitution inflammatory syndrome.

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