Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, Brussels, Belgium; Cellular and Molecular Immunology Lab, Brussels Center for Immunology (BCIM), Vrije Universiteit Brussel, Brussels, Belgium.
Institute for Medical Immunology, Université Libre de Bruxelles (ULB), Gosselies, Belgium; ULB Center for Research in Immunology (U-CRI), Gosselies, Belgium.
J Hepatol. 2024 Dec;81(6):1023-1039. doi: 10.1016/j.jhep.2024.07.007. Epub 2024 Jul 11.
BACKGROUND & AIMS: 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 leads to long-term alterations to the liver macrophage compartment.
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.
We show that T. brucei 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.
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.
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.
肝脏巨噬细胞发挥着各种稳态功能，是抵御病原体侵袭的重要防线。然而，目前尚不清楚肝脏内的感染病史是否会导致肝脏巨噬细胞群发生长期改变。
我们利用原生动物寄生虫布氏锥虫引起的可治愈感染模型，研究感染史是否能持久重塑肝巨噬细胞的特性和功能。我们采用了谱系示踪、单细胞 CITE-seq、单核多组学分析、表观基因组分析和功能测定相结合的方法，研究了在感染过程中和感染消退后肝巨噬细胞群的变化。
我们发现，布氏锥虫感染改变了肝脏驻留巨噬细胞的组成，导致单核细胞浸润，这些单核细胞分化为具有不同转录组特征的各种与感染相关的巨噬细胞群体。虽然感染相关的巨噬细胞在感染消退后消失，但单核细胞衍生的巨噬细胞在肝脏中定植，长期以来具有库普弗细胞（KC）样特征，并与胚胎期 KC 共存。值得注意的是，先前的感染经历在 KC 上留下了一个改变的转录程序，这是由 KC 染色质景观的表观遗传重塑和 KC 发生的转变，以及它们的生态位细胞的转录和表观遗传改变所支撑的。这种重编程改变了 KC 的功能，并与对随后的细菌感染的更高抵抗力有关。
我们的研究表明，先前暴露于寄生虫感染会诱导 KC 中的训练性免疫，从而在长期内重塑其特性和功能。
尽管肝脏在感染过程中经常受到影响，并且尽管它容纳了一个被称为库普弗细胞（KC）的主要常驻巨噬细胞群体，但目前尚不清楚感染是否能持久改变 KC 和它们的生态位细胞。我们的研究对先前治愈的寄生虫感染的长期影响进行了全面研究，揭示了 KC 及其生态位细胞的长期发生、表观遗传、转录组和功能变化，这些变化可能有助于 KC 重塑。我们的数据表明，感染史可能会在一生中不断地对 KC 进行重新编程，这可能对肝脏中的后续疾病易感性产生影响，影响预防和治疗方法。
