Gut Bacteria Drive Kupffer Cell Expansion via MAMP-Mediated ICAM-1 Induction on Sinusoidal Endothelium and Influence Preservation-Reperfusion Injury after Orthotopic Liver Transplantation
Gut Bacteria Drive Kupffer Cell Expansion via MAMP-Mediated ICAM-1 Induction on Sinusoidal Endothelium and Influence Preservation-Reperfusion Injury after Orthotopic Liver Transplantation
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DOI：
10.1016/j.ajpath.2012.09.010
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发表时间：
2013-01-01
影响因子：
6
通讯作者：
Demetris, Anthony J.
中科院分区：
文献类型：
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作者：
Corbitt, Natasha;Kimura, Shoko;Demetris, Anthony J.
肠道微生物组中的细菌将微生物相关分子模式（MAMP）释放到门静脉循环中，在那里它们通过低水平刺激增强全身免疫的各个方面。由于肝脏直接位于肠道下游，因此我们提出肠源性MAMPs塑造肝脏免疫并影响Kupffer细胞（KC）表型。无菌（GF），免疫治疗（AVMN），和常规（CL）小鼠被用来研究KC的发展，功能，并对冷藏，再灌注和原位移植的显着压力的反应。我们发现，鸡尾酒的生理活性MAMPs易位到门静脉循环，鞭毛蛋白（Toll样受体5配体）是最丰富的，能够促进肝单核细胞流入GF小鼠。在MAMP缺陷的GF或AVMN肝脏中，KCs的数量较低，具有较高的吞噬活性，并且具有较低的主要组织相容性复合体II表达。含MAMP的CL肝脏通过诱导肝窦内皮细胞间粘附分子1显著增加KC数量。这些CL KCs具有引发但预期的表型，具有增加的主要组织相容性复合物II类和较低的吞噬活性，增加了原位移植后对肝脏保存/再灌注损伤的易感性。KC数量、功能活性和成熟状态与肠源性MAMPs的浓度直接相关，并且可以通过广谱抗生素显著降低，从而影响对损伤的敏感性。(Am J Pathol 2013，182：180-191; http：//dx·doi·org/10·1016/j·ajpath·2012·09·010）
Bacteria in the gut microbiome shed microbial-associated molecule patterns (MAMPs) into the portal venous circulation, where they augment various aspects of systemic immunity via low-level stimulation. Because the liver is immediately downstream of the intestines, we proposed that gut-derived MAMPs shape liver immunity and affect Kupffer cell (KC) phenotype. Germ-free (GF), antibiotic-treated (AVMN), and conventional (CL) mice were used to study KC development, function, and response to the significant stress of cold storage, reperfusion, and orthotopic transplantation. We found that a cocktail of physiologically active MAMPs translocate into the portal circulation, with flagellin (Toll-like receptor 5 ligand) being the most plentiful and capable of promoting hepatic monocyte influx in GF mice. In MAMP-deficient GF or AVMN livers, KCs are lower in numbers, have higher phagocytic activity, and have lower major histocompatibility complex II expression. MAMP-containing CL livers harbor significantly increased KC numbers via induction of intercellular adhesion molecule 1 on liver sinusoidal endothelium. These CL KCs have a primed yet expected phenotype, with increased major histocompatibility complex class II and lower phagocytic activity that increases susceptibility to liver preservation/reperfusion injury after orthotopic transplantation. The KC number, functional activity, and maturational status are directly related to the concentration of gut-derived MAMPs and can be significantly reduced by broad-spectrum antibiotics, thereby affecting susceptibility to injury. (Am J Pathol 2013, 182: 180-191; http://dx.doi.org/10.1016/j.ajpath.2012.09.010)