Connecting liver and gut: Murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid

Abstract

Gut-activated T cells migrating into the liver can cause extraintestinal manifestations of inflammatory bowel disease. T cells acquire a gut-homing phenotype dependent on retinoic acid (RA) provided by intestinal dendritic cells (DC). We investigated whether liver antigen-presenting cells can induce gut tropism supporting an enterohepatic lymphocyte circulation. Priming of CD4+ T cells by liver sinusoidal endothelial cells (LSEC) supported migration into gut and gut-associated lymphoid tissue. As observed for T cells primed by intestinal DCs, this gut tropism depended on α4β7 integrin and CC chemokine receptor 9 (CCR9) expression by LSEC-primed CD4+ T cells. The induction of gut-homing molecules was mediated by RA, a derivate of vitamin A that is stored in large amounts within the liver. LSECs expressed functional retinal dehydrogenases and could convert vitamin A to RA. Conversely, the lack of signaling via the RA receptor prevented the expression of α4β7 integrin and CCR9 on LSEC-primed CD4+ T cells, consequently reducing their in vivo migration to the intestine. Other liver antigen-presenting cells failed to support high expression of α4β7 integrin on CD4+ T cells, thus, the potential to induce gut homing is restricted to LSECs. Conclusion: The capacity to promote gut tropism via vitamin A use is not unique for intestinal DCs but is also a feature of LSECs. Our data support the assumption that CD4+ T cells can migrate from the liver to the gut as one branch of a postulated enterohepatic lymphocyte circulation.

All-trans retinoic acid regulates hepatic bile acid homeostasis

“…Hepatic and ileal mRNA levels were normalized to the mRNA level of glyceraldehyde-3-phosphate dehydrogenase ( Gapdh ). Gapdh is considered a house keeping gene and frequently used as a reference gene [32, 33]. In addition, it has been shown that Gapdh is one of the most stable reference genes [34].…”

Mesenteric adipose tissue B lymphocytes promote local and hepatic inflammation in non‐alcoholic fatty liver disease mice

“…17 In our previous study, we proved that immune cells including T and B lymphocytes could shuttle from mesenteric lymph nodes to the liver and promote NAFLD. Studies have shown the existence of enterohepatic lymphocyte circulation.…”

The gut-liver axis: A busy two-way street

“…In addition to hepatic homing there was also significant homing to the small intestine. In the current article, Neumann et al7 demonstrate that priming of CD4+ T cells by LSEC resulted in a T‐cell phenotype that promoted homing to the intestine and the GALT, and this was largely dependent on very specific molecular events (Fig. 1).…”