Caspase-1 inCx3cr1-expressing cells drives an IL-18-dependent T cell response that promotes parasite control during acuteT. gondiiinfection
Authors: Babcock Isaac W. , Sibley Lydia A. , Labuzan Sydney A. , Cowan Maureen N. , Sethi Ish , Alemu Seblework , Kovacs Michael A. , Lukens John R. , Harris Tajie H. 
Published: January 2024

Inflammasome activation is a robust innate immune mechanism that promotes inflammatory responses through the release of alarmins and leaderless cytokines, including IL-1α, IL-1β, and IL-18. Various stimuli, including infectious agents and cellular stress, cause inflammasomes to assemble and activate caspase-1. Then, caspase-1 cleaves targets that lead to pore formation and leaderless cytokine activation and release.Toxoplasma gondiihas been shown to promote inflammasome formation, but the cell types utilizing caspase-1 and the downstream effects on immunological outcomes during acutein vivoinfection have not been explored. Here, using knockout mice, we examine the role of caspase-1 responses during acuteT. gondiiinfection globally and inCx3cr1-positive populations. We providein vivoevidence that caspase-1 expression is critical for, IL-18 release, optimal interferon-γ (IFN-ψ) production, monocyte and neutrophil recruitment to the site of infection, and parasite control. Specifically, we find that caspase-1 expression inCx3cr1-positive cells drives IL-18 release, which potentiates CD4+T cell IFN-γ production and parasite control. Notably, ourCx3cr1-Casp1knockouts exhibited a selective T cell defect, mirroring the phenotype observed inIl18knockouts. In further support of this finding, treatment ofCx3cr1-Casp1knockout mice with recombinant IL-18 restored CD4+T cell IFN-γ responses and parasite control. Additionally, we show that neutrophil recruitment is dependent on IL-1 receptor accessory protein (IL-1RAP) signaling but is dispensable for parasite control. Overall, these experiments highlight the multifaceted role of caspase-1 in multiple cell populations contributing to specific pathways that collectively contribute to caspase-1 dependent immunity toT. gondii.

AUTHOR SUMMARY

When a cell undergoes inflammatory cell death, termed pyroptosis, cellular content is released and has the potential to stimulate immune responses. Our work highlights that in the context ofT. gondiiinfection, distinct cell populations undergo pyroptosis each of which has different impacts on how the immune system responds. These findings suggest a collaborative effort of multiple cell types undergoing pyroptosis for optimal immunity to infection. Using a cell-type specific knockout to render macrophages incapable of undergoing pyroptosis, we find that macrophage pyroptosis reinforces adaptive immune cell function, while other population’s pyroptosis stimulates the recruitment of innate immune cells into the infected tissue. We go on to identify a specific molecule, IL-18, is released from macrophage pyroptosis that reinforces adaptive immune cell function. By reintroducing IL-18 into the macrophage knockout mice, we successfully restored adaptive immune cell function thereby facilitating the recovery of parasite control. This study outlines the impact of pyroptosis on immunity toT. gondiiand stratifies the effects from separate cell populations and their associated downstream pathways.