Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis
Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis
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DOI：
10.1016/j.immuni.2020.06.003
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发表时间：
2020-09-15
期刊：
影响因子：
32.4
通讯作者：
Gautier, Emmanuel L.
中科院分区：
文献类型：
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作者：
Tran, Sophie;Baba, Ines;Gautier, Emmanuel L.
枯否细胞（KCs）是肝脏驻留的巨噬细胞，其在成人中独立于单核细胞通过增殖进行自我更新。然而，它们在非酒精性脂肪性肝炎（NASH）期间如何维持仍然不清楚。我们发现在NASH期间，一部分KC来源于Ly-6C（+）单核细胞，这是KC自我更新受损的基础。随着疾病进展，单核细胞来源的KC（MoKC）逐渐接种KC池，以响应胚胎来源的KC（EmKC）死亡。与EmKCs相比，这些MoKCs部分不成熟，并表现出促炎状态。然而，他们长期移植KC池，因为他们在获得成熟EmKC标记物的同时保持疾病消退。虽然KC作为一个整体有利于NASH期间肝脏甘油三酯的储存，但EmKC比MoKC更有效地促进它，后者加剧了肝损伤，突出了不同来源的KC之间的功能差异。总的来说，我们的数据表明，KC稳态在NASH期间受损，改变了肝脏对脂质的反应，以及KC个体发育。
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.