Evidence of inflammasome activation and formation of monocyte-derived ASC specks in HIV-1 positive patients
The formation of large intracellular protein aggregates of the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain; also know as PYCARD) is a hallmark of inflammasome activation. ASC speck-forming cells release the highly proinflammatory cytokine IL-1β in addition to ASC specks into the extracellular space during pyroptotic cell death. There ASC specks can propagate inflammation to other nonactivated cells or tissues. HIV-1 retroviral infection triggers inflammasome activation of abortively infected CD4+ T cells in secondary lymphatic tissues. However, if pyroptosis occurs in other peripheral blood mononuclear cells (PBMCs) of HIV-1-infected patients is currently unknown. We investigated if ASC speck positive cells are present in the circulation of HIV-1-infected patients.Design and methods:
PBMCs or plasma of HIV-1 infected, antiretroviral therapy-naive patients were analyzed for the presence of ASC speck+ cells or extracellular ASC and compared with healthy controls. Intracellular staining for ASC was employed to detect ASC speck+ cells within PBMCs by flow cytometry, and ELISA to detect free ASC in the plasma. ASC multimerization was confirmed by immunoblot.Results:
Peripheral blood CD14++CD16− monocytes were ASC speck+ in HIV patients, but not in healthy controls. In the subgroup analysis, HIV patients with lower CD4+ T-cell counts and higher viral load had significantly more ASC speck+ monocytes. ASC speck formation did not correlate with Gag expression, coinfection, lactate dehydrogenase or C-reactive protein.Conclusion:
Our findings suggest that pyroptotic CD14++CD16− classical monocytes of HIV-1-infected patients release ASC specks into the blood stream, a phenomenon that may contribute to HIV-1 induced inflammation and immune activation.