目的:肝巨噬细胞具有多种体内平衡功能,是抵御致病性损伤的重要防线。然而,目前尚不清楚肝脏感染性疾病史是否指示肝脏巨噬细胞区室的长期改变.
方法:我们利用由原生动物寄生虫布氏锥虫引起的寄生虫感染的可治愈模型来研究感染史是否可以持久地重塑肝巨噬细胞的身份和功能。采用命运映射的组合,单细胞CITE测序,单核多体组分析,表观基因组分析,和功能测定,我们研究了感染消退期间和之后肝巨噬细胞区室的改变。
结果:我们发现布氏T.b.感染改变了肝脏常驻巨噬细胞的组成,导致分化为各种感染相关巨噬细胞群体的单核细胞浸润,这些巨噬细胞群体具有不同的转录组学特征。而与感染相关的巨噬细胞在感染消退后消失,单核细胞来源的巨噬细胞移植入肝脏,假设Kupffer细胞(KC)样特征,并与胚胎KC长期共存。值得注意的是,先前暴露于感染后的KC上的转录程序改变了,这是由KC染色质景观的表观遗传重塑和KC个体发育的转变所支撑的,以及它们小生境细胞的转录和表观遗传改变。这种重编程改变了KC功能,并与对随后的细菌感染的抵抗力增强有关。
结论:我们的研究表明,先前暴露于寄生虫感染可诱导KC中的训练免疫,从长远来看,重塑他们的身份和功能。
■尽管肝脏在感染过程中经常受到影响,尽管有大量的常驻巨噬细胞被称为Kupffer细胞(KCs),目前尚不清楚感染是否能持久改变KCs及其小生境细胞.我们的研究提供了一个全面的调查,治愈寄生虫感染,揭幕持久的本体,表观遗传,KC和KC生态位细胞的转录组和功能变化,这可能有助于KC重塑。我们的数据表明,感染史可能会在整个生命中不断重新编程KC,对随后的肝脏疾病易感性有潜在的影响。影响预防和治疗方法。
OBJECTIVE: Liver macrophages fulfill various homeostatic functions and represent an essential line of defense against pathogenic insults. However, it remains unclear whether a history of infectious disease in the liver instructs long-term alterations to the liver macrophage compartment.
METHODS: We utilized a curable model of parasitic infection invoked by the protozoan parasite Trypanosoma brucei brucei to investigate whether infection history can durably reshape hepatic macrophage identity and function. Employing a combination of fate mapping, single cell CITE-sequencing, single nuclei multiome analysis, epigenomic analysis, and functional assays, we studied the alterations to the liver macrophage compartment during and after the resolution of infection.
RESULTS: We show that T. b. brucei infection alters the composition of liver-resident macrophages, leading to the infiltration of monocytes that differentiate into various infection-associated macrophage populations with divergent transcriptomic profiles. Whereas infection-associated macrophages disappear post-resolution of infection, monocyte-derived macrophages engraft in the liver, assume a Kupffer cell (KC)-like profile and co-exist with embryonic KCs in the long-term. Remarkably, the prior exposure to infection imprinted an altered transcriptional program on post-resolution KCs that was underpinned by an epigenetic remodeling of KC chromatin landscapes and a shift in KC ontogeny, along with transcriptional and epigenetic alterations in their niche cells. This reprogramming altered KC functions and was associated with increased resilience to a subsequent bacterial infection.
CONCLUSIONS: Our study demonstrates that a prior exposure to a parasitic infection induces trained immunity in KCs, reshaping their identity and function in the long-term.
UNASSIGNED: Although the liver is frequently affected during infections, and despite housing a major population of resident macrophages known as Kupffer cells (KCs), it is currently unclear whether infections can durably alter KCs and their niche cells. Our study provides a comprehensive investigation into the long-term impact of a prior, cured parasitic infection, unveiling long-lasting ontogenic, epigenetic, transcriptomic and functional changes to KCs as well as KC niche cells, which may contribute to KC remodeling. Our data suggest that infection history may continuously reprogram KCs throughout life with potential implications for subsequent disease susceptibility in the liver, influencing preventive and therapeutic approaches.