枯否细胞自我更新受损改变了非酒精性脂肪性肝炎中肝脏对脂质过载的反应。

Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis.

机构信息

Institut National de la Santé et de la Recherche Médicale (Inserm, UMR_S 1166), Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France.

Institut National de la Santé et de la Recherche Médicale (Inserm, UMR_S 1269), Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France.

出版信息

Immunity. 2020 Sep 15;53(3):627-640.e5. doi: 10.1016/j.immuni.2020.06.003. Epub 2020 Jun 19.

DOI:10.1016/j.immuni.2020.06.003

PMID:32562600

Abstract

Kupffer cells (KCs) are liver-resident macrophages that self-renew by proliferation in the adult independently from monocytes. However, how they are maintained during non-alcoholic steatohepatitis (NASH) remains ill defined. We found that a fraction of KCs derived from Ly-6C monocytes during NASH, underlying impaired KC self-renewal. Monocyte-derived KCs (MoKCs) gradually seeded the KC pool as disease progressed in a response to embryo-derived KC (EmKC) death. Those MoKCs were partly immature and exhibited a pro-inflammatory status compared to EmKCs. Yet, they engrafted the KC pool for the long term as they remained following disease regression while acquiring mature EmKC markers. While KCs as a whole favored hepatic triglyceride storage during NASH, EmKCs promoted it more efficiently than MoKCs, and the latter exacerbated liver damage, highlighting functional differences among KCs with different origins. Overall, our data reveal that KC homeostasis is impaired during NASH, altering the liver response to lipids, as well as KC ontogeny.

摘要

库普弗细胞（KCs）是肝脏驻留的巨噬细胞，在成人中可通过增殖自我更新，而不依赖于单核细胞。然而，在非酒精性脂肪性肝炎（NASH）中它们是如何被维持的仍不清楚。我们发现，在 NASH 期间，一部分 KCs 来源于 Ly-6C 单核细胞，这导致了 KC 自我更新受损。随着疾病的进展，单核细胞衍生的 KCs（MoKCs）逐渐取代 KC 池，这是对胚胎衍生的 KC（EmKC）死亡的反应。与 EmKCs 相比，这些 MoKCs 部分不成熟，并表现出促炎状态。然而，它们在疾病消退后仍长期定植于 KC 池，同时获得成熟的 EmKC 标志物。虽然整体而言，KCs 在 NASH 期间有利于肝脏甘油三酯的储存，但 EmKCs 比 MoKCs 更有效地促进了这一过程，而后者则加剧了肝损伤，突出了具有不同起源的 KC 之间的功能差异。总的来说，我们的数据揭示了在 NASH 期间 KC 稳态受到损害，改变了肝脏对脂质的反应以及 KC 的个体发生。