*For medical professionals only
The liver and intestine are good neighbors, and there is a direct passage between them to each other's homes, the portal vein, which allows nutrients from the intestines, intestinal bacteria and their metabolites, and pathogens to enter the liver directly.
In order to prevent the good neighbor from sending miscellaneous things and causing him to fall into an accident and develop excessive inflammation, the liver has set up a firewall for the intestines in the portal vein.
Recently, the latest study published in the journal Nature by Masaru Ishii et al. of Osaka University in Japan revealed that there is a special liver-resident macrophage in the portal vein region of the liver, which has immunosuppressive properties and relies on an intestinal microbiota and its metabolites associated with the longevity of centenarians to inhibit the inflammatory response of the liver. The presence of these macrophages is particularly critical to prevent hepatitis, especially when the intestinal barrier is compromised.
Screenshot of the first page of the paper
Different regions of the liver, especially the portal vein (PV) and central vein (CV), exhibit significant cell distribution and functional heterogeneity. Understanding how immune cells differ in different regions is critical to the liver's metabolic and immunomodulatory functions.
In this study, Masaru Ishii and colleagues first performed single-cell transcriptomic analysis on mouse liver samples to finely distinguish macrophages from the hepatic portal vein region versus the central venous region to observe the heterogeneity of macrophage gene expression at the cellular level.
They found a specific subset of macrophages, mainly concentrated in the portal region of the liver, showing significant anti-inflammatory properties, characterized by high expression of the scavenger receptor Marco protein (Marco+) and high expression of anti-inflammatory cytokines such as IL-10, which inhibits the excessive aggregation of neutrophils that mediate the inflammatory response. With these liver-resident macrophages, the level of neutrophil infiltration in the hepatic portal vein is significantly lower than in the central venous area, both in injury and in a stable state.
There are few centriolocytes in the PV area
By comparing mice with different intestinal colonizations, the researchers revealed that the immunosuppressive function of these macrophages is dependent on a specific family of intestinal bacteria, Odoribacteraceae (Odori). Odori activates specific signaling pathways of macrophages in the portal vein through its metabolite isoallo-LCA, prompting them to express Marco protein to enhance their anti-inflammatory ability, and the abundance of intestinal colonization of Odori is positively correlated with the level of Marco+ liver-resident macrophages.
Marco proteins are members of the scavenger receptor family and are only expressed on specific types of macrophages. By recognizing and responding to damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), Marco helps regulate the body's immune response, control inflammation and promote tissue recovery. In liver-resident macrophage cells that received Odori's letter, Marco's signaling further stimulated the production of anti-inflammatory cytokines such as IL-10, inhibiting neutrophil adhesion in the portal vein region to reduce its aggregation.
Oral administration of isoallo-LCA to mice can induce liver-resident macrophages to express Marco and increase the expression level of IL-10.
It is worth noting that the colonization abundance of Odori has been shown to be associated with longevity in centenarians in recent years [2], and it seems that the effects of Odori and isoallo-LCA on human immunity are indeed something.
Odori 及其代 谢物isoallo-LCA是解锁 She never asked me
As for why Marco+ macrophages are mainly found in the portal vein of the liver rather than the central vein, researchers believe that the root cause is to guard against the gut. Blood from the intestine can pass directly through the portal vein to the liver, a mechanism that makes the liver more susceptible to intestinal microbial imbalances, which can lead to a variety of inflammatory liver diseases when intestinal infections occur.
Therefore, the researchers further observed that Marco+ liver-resident macrophages play a key role in regulating the hepatic immune response, especially in the immunosuppressive and anti-inflammatory processes in the hepatic portal vein region. Knockout of Marco resulted in a significant increase in inflammatory lymphocytes (TH17 cells) and neutrophils in the liver of mice with chronic colitis, as well as an increase in serum markers of liver injury and liver fibrosis.
The liver inflammatory response increased after Marco knockout
If nonalcoholic fatty liver disease (NAFLD) was induced by abnormal accumulation of liver lipids in mice by adjusting the diet, it was observed that the Marco+ liver-resident macrophages in mice decreased by 64.5% after two weeks of feeding. In mice with missing Marco expression, this diet induces more severe liver inflammation and increased periportal steatosis.
In addition, the total number of macrophages was comparable in liver samples from patients with nonalcoholic fatty liver disease or primary sclerosing cholangitis (PSC) compared to healthy controls, but the number of Marco+ macrophages was reduced.
These findings suggest that Marco+ liver-resident macrophages are associated with chronic inflammatory liver disease.
The proportion of Marco-expressing macrophages in the liver of PSC patients is reduced
From a clinical point of view, this study has found a special line of defense for the gut set by the liver, providing a new target for the treatment and prevention of common and refractory liver diseases such as non-alcoholic fatty liver disease, and may bring hope to patients in the future by modulating the gut microbiota or directly using the anti-inflammatory ability of Marco+ liver-resident macrophages.
Bibliography:
[1] Miyamoto, Y., Kikuta, J., Matsui, T. et al. Periportal macrophages protect against commensal-driven liver inflammation. Nature (2024). https://doi.org/10.1038/s41586-024-07372-6
[2] Sato, Y. et al. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature 599, 458–464 (2021).
The author of this article丨Zhang Aidi