Caspase-1 in Cx3cr1-expressing cells drives an IL-18-dependent T cell response that promotes parasite control during acute Toxoplasma gondii infection.

IF 5.5 1区 医学 Q1 MICROBIOLOGY
PLoS Pathogens Pub Date : 2024-10-24 eCollection Date: 2024-10-01 DOI:10.1371/journal.ppat.1012006
Isaac W Babcock, Lydia A Sibley, Sydney A Labuzan, Maureen N Cowan, Ish Sethi, Seblework Alemu, Abigail G Kelly, Michael A Kovacs, John R Lukens, Tajie H Harris
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引用次数: 0

Abstract

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 gondii has been shown to promote inflammasome formation, but the cell types utilizing caspase-1 and the downstream effects on immunological outcomes during acute in vivo infection have not been explored. Here, using knockout mice, we examine the role of caspase-1 responses during acute T. gondii infection globally and in Cx3cr1-positive populations. We provide in vivo evidence that caspase-1 expression is critical for, IL-18 release, optimal interferon-γ (IFN-γ) production, monocyte and neutrophil recruitment to the site of infection, and parasite control. Specifically, we find that caspase-1 expression in Cx3cr1-positive cells drives IL-18 release, which potentiates CD4+ T cell IFN-γ production and parasite control. Notably, our Cx3cr1-Casp1 knockouts exhibited a selective T cell defect, mirroring the phenotype observed in Il18 knockouts. In further support of this finding, treatment of Cx3cr1-Casp1 knockout 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 to T. gondii.

Cx3cr1表达细胞中的Caspase-1驱动IL-18依赖性T细胞反应,从而在弓形虫急性感染期间促进对寄生虫的控制。
炎症小体激活是一种强大的先天性免疫机制,它通过释放alarmins和无领导细胞因子(包括IL-1α、IL-1β和IL-18)来促进炎症反应。各种刺激(包括感染性病原体和细胞应激)会导致炎性体聚集并激活 caspase-1。然后,caspase-1 分解靶标,导致孔隙形成和无领导细胞因子的激活和释放。弓形虫已被证明能促进炎症小体的形成,但在体内急性感染过程中,利用caspase-1的细胞类型及其对免疫学结果的下游影响尚未被探索。在这里,我们利用基因敲除小鼠研究了在全球范围内以及在 Cx3cr1 阳性群体中,Caspase-1 在淋球菌急性感染过程中的作用。我们提供的体内证据表明,caspase-1 的表达对 IL-18 的释放、干扰素-γ(IFN-γ)的最佳产生、单核细胞和中性粒细胞被招募到感染部位以及寄生虫控制至关重要。具体来说,我们发现 Cx3cr1 阳性细胞中的 caspase-1 表达会驱动 IL-18 的释放,从而促进 CD4+ T 细胞 IFN-γ 的产生和寄生虫的控制。值得注意的是,我们的 Cx3cr1-Casp1 基因敲除子表现出选择性 T 细胞缺陷,这与在 Il18 基因敲除子中观察到的表型如出一辙。为进一步证实这一发现,用重组 IL-18 处理 Cx3cr1-Casp1 基因敲除小鼠可恢复 CD4+ T 细胞 IFN-γ 反应和寄生虫控制。此外,我们还发现中性粒细胞的募集依赖于 IL-1 受体附属蛋白(IL-1RAP)信号,但对寄生虫的控制来说是不可或缺的。总之,这些实验凸显了 caspase-1 在多个细胞群中的多方面作用,这些细胞群对特定途径做出了贡献,共同促成了 caspase-1 对淋球菌的依赖性免疫。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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