Role for Caspase-8 in the Release of IL-1β and Active Caspase-1 from Viable Human Monocytes during Toxoplasma gondii Infection

Author:

Pandori William J.1,Matsuno Stephanie Y.1ORCID,Shin Ji-Hun1ORCID,Kim Samuel C.1,Kao Tiffany H.1,Mallya Sharmila1,Batarseh Sarah N.1,Lodoen Melissa B.1ORCID

Affiliation:

1. Department of Molecular Biology & Biochemistry and the Institute for Immunology, University of California, Irvine, CA

Abstract

Abstract Monocytes are actively recruited to sites of infection and produce the potent proinflammatory cytokine IL-1β. We previously showed that IL-1β release during Toxoplasma gondii infection of primary human monocytes requires the NLRP3 inflammasome and caspase-1 but is independent of gasdermin D and pyroptosis. To investigate mechanisms of IL-1β release, we generated caspase-1, -4, -5, or -8 knockout (KO) THP-1 monocytic cells. Genetic ablation of caspase-1 or -8, but not caspase-4 or -5, decreased IL-1β release during T. gondii infection without affecting cell death. In contrast, TNF-α and IL-6 secretion were unperturbed in caspase-8 KO cells during T. gondii infection. Dual pharmacological inhibition of caspase-8 and RIPK1 in primary monocytes also decreased IL-1β release without affecting cell viability or parasite infection. Caspase-8 was also required for the release of active caspase-1 from T. gondii–infected cells and for IL-1β release during infection with the related apicomplexan parasite Neospora caninum. Surprisingly, caspase-8 deficiency did not impair synthesis or cleavage of pro–IL-1β, but resulted in the retention of mature IL-1β within cells. Generation of gasdermin E KO and ATG7 KO THP-1 cells revealed that the release of IL-1β was not dependent on gasdermin E or ATG7. Collectively, our data indicate that during T. gondii Infection of human monocytes, caspase-8 functions in a novel gasdermin-independent mechanism controlling IL-1β release from viable cells. This study expands on the molecular pathways that promote IL-1β in human immune cells and provides evidence of a role for caspase-8 in the mechanism of IL-1β release during infection.

Funder

HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases

Publisher

The American Association of Immunologists

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