Sustained sensing of commensal-derived products directs polarized immune cell positioning within the liver to optimize host defense

ABSTRACT: The liver is located at the interface between the intestinal portal vasculature and the general circulation, employing a complex set of innate and adaptive immune cells to protect from the continuous systemic threat of gut-translocating pathogens. In contrast to lymphoid tissues in which asymmetric, polarized spatial positioning of distinct cell types plays an essential role in optimal host defense, the relationship between liver phagocytes and lymphoid element distribution and their immune functions is currently unknown. This lack of organization stands in marked contrast to the extensively documented zonation of hepatocyte metabolic function controlled by Wnt signaling during development. Here we used quantitative multi-parameter confocal imaging to re-examine resident immune cells distribution in the liver, finding that both myeloid (Kupffer cell -KC) and lymphoid (NKT cell) components are substantially enriched in the peri-portal regions of the liver lobule, the entry point for portal venous blood rich in gut-derived pathogens and molecules. Peri-portal immune enrichment of KCs was lost in germ-free (GF) animals and coincided temporally with weaning and microbial colonization, suggesting that immune cell positioning was not a developmentally programmed process but rather dependent on extrinsic factors. Conditional ablation of MyD88-dependent bacterial product sensing by liver sinusoidal endothelial cells (LSECs) disrupted KC spatial organization animals, consistent with immune cell positioning within the liver architecture arising from sustained, active responses of LSECs to microbial stimuli. Bacterial challenge studies revealed that this asymmetric peri-portal-biased immune cell localization protects the liver and the host against bacterial dissemination. Together, these data reveal that LSECs act as microbiome sensors, actively promoting concentration of protective immune components in the sub-regions of the liver most susceptible to infection to provide optimal host defense against systemic pathogen spread.

ORGANISM(S): Mus musculus

PROVIDER: GSE144087 | GEO | 2020/07/31

REPOSITORIES: GEO