The liver connects the intestinal portal vasculature with the general circulation. It consists of hexagonal units called lobules that not only ensure efficient metabolism but also organize immune cells in a strategic topographical distribution.
The metabolic zonation of the liver is a very well-described functional process. However, the benefits of immune zonation and how the microbiome shapes the host response is still unknown.
A paper by Gola and colleagues published recently in Nature, demonstrated that liver sinusoidal endothelial cells (LSECs) organize immune cells into anatomical immune zones by forming chemokine gradients. The authors showed that Kupffer cells (KCs), innate lymphoid cells, and dendritic cells are recruited and retained by chemokine gradients in the portal tract, a highly important mechanism for killing pathogens that have escaped the detection in the gut.
Multiplex imaging, built around immunohistochemistry, demonstrated that myeloid (i.e. F4/80+ Tim4+ KCs) and lymphoid resident cells concentrated around periportal regions.
Further analysis in germ-free mice revealed that immune zonation is a dynamic process and is dependent on gut microbiota.
Using genetically manipulated mice, the authors demonstrated that LSECs can sense microbial products via MyD88 signalling and subsequently coordinate immune zonation in the liver lobules.
RNA sequencing showed that chemokines such as CXCL9 and its cognate receptor CXCR3 are enriched in the periportal region.
Gene set enrichment analysis (GSEA), heparan sulphate and hyaluronic acid staining, revealed that chemokines such as CXCL9 bind to components of the glycocalyx to create spatial gradients for the immune cells.
Listeria infection-based assays indicated that periportal positioning of KCs has a critical role in protecting the host from bacterial dissemination and sepsis.
Mathematical modelling analysed the effect of spatial localization of KCs on their ability to capture pathogens coming from the portal vein.
In this study, the authors demonstrated that LSECs sense the microbiome, actively driving immune cells to optimize host defence. They also showed that the so-called ‘zonal barrier 1’ located in the periportal lobular region not only removes pathogens, but also prevents damage spreading to the metabolically critical cells around the central vein in acinar zone 3.
These analyses suggested that therapies aimed at modulating chemokine gradients, such as chemokine mimetics, may be more effective than those aimed at inhibiting their secretion (i.e., through GPCR inhibition), an approach that has been problematic.
Gola, A., Dorrington, M.G., Speranza, E. et al. (2021). Commensal-driven immune zonation of the liver promotes host defence. Nature 589, 131-136