Immune Cell Trafficking to the Liver

Abstract

The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.

Figure 1:

Blood Circulation to the Liver: The possesses a unique dual circulation, receiving blood both from the systemic arterial system via the hepatic artery and from the mesenteric system via the portal vein. This arrangement allows the liver to monitor and process substrates from both areas of the body and to release appropriate products systemically. Adapted with permission from Current Surgical Therapy, 12^th Edition p. 393.

Figure 2:

Microcirculation of hepatic lobule. Terminal branches of the hepatic artery and portal vein both drain into liver sinusoids where blood is then carried to the central vein, a branch of the hepatic vein. Multiple sets of hepatic artery and portal vein branches drain into a single central vein. Adapted with permission from Juza et al. Clin Anat 2014;27(5):764–769.²⁵⁶

Figure 3.

Resident Immune Cells within Liver. The liver is home to cells with a diversity of immunologic functions. Antigens from systemic and portal circulation are carried into the sinusoids where they are met by resident KCs, lymphocytes, dendritic cells, and HSCs. LSECs line the sinusoids and can also present antigens to activate the immune system. Within the sinusoids are fenestrations where antigens can extrude into the Space of Disse and also through which hepatocytes can sample antigens within sinusoidal lumen. Lymphocytes also reside within the parenchyma amongst hepatocytes. Adapted from with permission from Crispe, Nat Rev Immunol, 2003;3(1):51–62.

Figure 4.

A schematic representation of adhesion molecules within liver sinusoids. LSECs express a number of adhesion molecules, including VCAM-1, MadCAM-1, and ICAM-1 that bind to the integrins α4β1, α4β7, and the β2 family. VCAM-1 is expressed at levels within sinusoids that other tissues only express under inflammatory conditions. ICAM-1 is also expressed by LSECs at levels that are normally seen in post-capillary venules. MadCAM-1 is normally only expressed in the gut, directing immune cells to the intestine; however, this becomes an important mediator in PSC when aberrantly expressed by LSECs. ICAM-1 is expressed on the basal membrane, whereas VCAM-1 and MadCAM-1 are expressed on the luminal membrane.