PDF(Pubmed)
Abstract：
UNASSIGNED: Protective immunity against intestinal helminths requires induction of robust type-2 immunity orchestrated by various cellular and soluble effectors which promote goblet cell hyperplasia, mucus production, epithelial proliferation, and smooth muscle contractions to expel worms and re-establish immune homeostasis. Conversely, defects in type-2 immunity result in ineffective helminth clearance, persistent infection, and inflammation. Macrophages are highly plastic cells that acquire an alternatively activated state during helminth infection, but they were previously shown to be dispensable for resistance to Trichuris muris infection.
UNASSIGNED: We use the in vivo mouse model A20myel-KO, characterized by the deletion of the potent anti-inflammatory factor A20 (TNFAIP3) specifically in the myeloid cells, the excessive type-1 cytokine production, and the development of spontaneous arthritis. We infect A20myel-KO mice with the gastrointestinal helminth Trichuris muris and we analyzed the innate and adaptive responses. We performed RNA sequencing on sorted myeloid cells to investigate the role of A20 on macrophage polarization and type-2 immunity. Moreover, we assess in A20myel-KO mice the pharmacological inhibition of type-1 cytokine pathways on helminth clearance and the infection with Salmonella typhimurium.
UNASSIGNED: We show that proper macrophage polarization is essential for helminth clearance, and we identify A20 as an essential myeloid factor for the induction of type-2 immune responses against Trichuris muris. A20myel-KO mice are characterized by persistent Trichuris muris infection and intestinal inflammation. Myeloid A20 deficiency induces strong classical macrophage polarization which impedes anti-helminth type-2 immune activation; however, it promotes detrimental Th1/Th17 responses. Antibody-mediated neutralization of the type-1 cytokines IFN-γ, IL-18, and IL-12 prevents myeloid-orchestrated Th1 polarization and re-establishes type-2-mediated protective immunity against T. muris in A20myel-KO mice. In contrast, the strong Th1-biased immunity in A20myel-KO mice offers protection against Salmonella typhimurium infection.
UNASSIGNED: We hereby identify A20 as a critical myeloid factor for correct macrophage polarization and appropriate adaptive mucosal immunity in response to helminth and enteric bacterial infection.
UNASSIGNED: We use the in vivo mouse model A20myel-KO, characterized by the deletion of the potent anti-inflammatory factor A20 (TNFAIP3) specifically in the myeloid cells, the excessive type-1 cytokine production, and the development of spontaneous arthritis. We infect A20myel-KO mice with the gastrointestinal helminth Trichuris muris and we analyzed the innate and adaptive responses. We performed RNA sequencing on sorted myeloid cells to investigate the role of A20 on macrophage polarization and type-2 immunity. Moreover, we assess in A20myel-KO mice the pharmacological inhibition of type-1 cytokine pathways on helminth clearance and the infection with Salmonella typhimurium.
UNASSIGNED: We show that proper macrophage polarization is essential for helminth clearance, and we identify A20 as an essential myeloid factor for the induction of type-2 immune responses against Trichuris muris. A20myel-KO mice are characterized by persistent Trichuris muris infection and intestinal inflammation. Myeloid A20 deficiency induces strong classical macrophage polarization which impedes anti-helminth type-2 immune activation; however, it promotes detrimental Th1/Th17 responses. Antibody-mediated neutralization of the type-1 cytokines IFN-γ, IL-18, and IL-12 prevents myeloid-orchestrated Th1 polarization and re-establishes type-2-mediated protective immunity against T. muris in A20myel-KO mice. In contrast, the strong Th1-biased immunity in A20myel-KO mice offers protection against Salmonella typhimurium infection.
UNASSIGNED: We hereby identify A20 as a critical myeloid factor for correct macrophage polarization and appropriate adaptive mucosal immunity in response to helminth and enteric bacterial infection.
摘要：
■针对肠蠕虫的保护性免疫需要诱导由各种细胞和可溶性效应子协调的强大的2型免疫，这些效应子促进杯状细胞增生，粘液产生，上皮增殖，和平滑肌收缩以排出蠕虫并重新建立免疫稳态。相反，2型免疫缺陷导致无效的蠕虫清除，持续性感染,和炎症。巨噬细胞是高度可塑性的细胞，在蠕虫感染期间获得交替活化状态，但是以前被证明对Trichurismuris感染的抵抗力是可有可无的。
■我们使用体内小鼠模型A20myel-KO，其特征是在骨髓细胞中特异性缺失有效的抗炎因子A20（TNFAIP3），过度的1型细胞因子产生，和自发性关节炎的发展。我们用胃肠道蠕虫Trichurismuris感染A20myel-KO小鼠，并分析了先天和适应性反应。我们对分选的骨髓细胞进行RNA测序，以研究A20对巨噬细胞极化和2型免疫的作用。此外，我们在A20myel-KO小鼠中评估了1型细胞因子途径对蠕虫清除和鼠伤寒沙门氏菌感染的药理学抑制作用。
■我们表明，适当的巨噬细胞极化对于清除蠕虫至关重要，我们确定A20是诱导针对毛虫的2型免疫反应的必需髓样因子。A20myel-KO小鼠的特征在于持续的毛虫感染和肠道炎症。髓样A20缺乏诱导强经典巨噬细胞极化，阻碍抗蠕虫2型免疫激活；然而，它促进有害的Th1/Th17反应。抗体介导的1型细胞因子IFN-γ的中和，IL-18和IL-12在A20myel-KO小鼠中预防骨髓协调的Th1极化并重建2型介导的针对T.muris的保护性免疫。相比之下,A20myel-KO小鼠的强Th1偏向性免疫提供了对抗鼠伤寒沙门氏菌感染的保护。
■我们在此确定A20是响应于蠕虫和肠道细菌感染的正确巨噬细胞极化和适当的适应性粘膜免疫的关键髓样因子。
■我们使用体内小鼠模型A20myel-KO，其特征是在骨髓细胞中特异性缺失有效的抗炎因子A20（TNFAIP3），过度的1型细胞因子产生，和自发性关节炎的发展。我们用胃肠道蠕虫Trichurismuris感染A20myel-KO小鼠，并分析了先天和适应性反应。我们对分选的骨髓细胞进行RNA测序，以研究A20对巨噬细胞极化和2型免疫的作用。此外，我们在A20myel-KO小鼠中评估了1型细胞因子途径对蠕虫清除和鼠伤寒沙门氏菌感染的药理学抑制作用。
■我们表明，适当的巨噬细胞极化对于清除蠕虫至关重要，我们确定A20是诱导针对毛虫的2型免疫反应的必需髓样因子。A20myel-KO小鼠的特征在于持续的毛虫感染和肠道炎症。髓样A20缺乏诱导强经典巨噬细胞极化，阻碍抗蠕虫2型免疫激活；然而，它促进有害的Th1/Th17反应。抗体介导的1型细胞因子IFN-γ的中和，IL-18和IL-12在A20myel-KO小鼠中预防骨髓协调的Th1极化并重建2型介导的针对T.muris的保护性免疫。相比之下,A20myel-KO小鼠的强Th1偏向性免疫提供了对抗鼠伤寒沙门氏菌感染的保护。
■我们在此确定A20是响应于蠕虫和肠道细菌感染的正确巨噬细胞极化和适当的适应性粘膜免疫的关键髓样因子。
