期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 6, 期 237, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3008618
关键词
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资金
- Swiss National Science Foundation [310030-124732, 313600-123736]
- Canadian Institutes of Health Research
- Genaxen Foundation
- Astra-Altana research funding
- Swiss Cancer League
- Swiss National Foundation [313600-123736/1, 138392]
- ERC Starting Grant from the European Research Council
- European Union's Seventh Framework Programme
- ERC Grant Agreements [281904, 281785]
- Swiss National Science Foundation (SNF) [310030_124732] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [281785, 281904] Funding Source: European Research Council (ERC)
A prerequisite for establishment of mutualism between the host and the microbial community that inhabits the large intestine is the stringent mucosal compartmentalization of microorganisms. Microbe-loaded dendritic cells trafficking through lymphatics are arrested at the mesenteric lymph nodes, which constitute the firewall of the intestinal lymphatic circulation. We show in different mouse models that the liver, which receives the intestinal venous blood circulation, forms a vascular firewall that captures gut commensal bacteria entering the bloodstream during intestinal pathology. Phagocytic Kupffer cells in the liver of mice clear commensals from the systemic vasculature independently of the spleen through the liver's own arterial supply. Damage to the liver firewall inmice impairs functional clearance of commensals from blood, despite heightened innate immunity, resulting in spontaneous priming of nonmucosal immune responses through increased systemic exposure to gut commensals. Systemic immune responses consistent with increased extraintestinal commensal exposure were found in humans with liver disease (nonalcoholic steatohepatitis). The liver may act as a functional vascular firewall that clears commensals that have penetrated either intestinal or systemic vascular circuits.
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