Biliary Obstruction Selectively Expands and Activates Liver Myeloid Dendritic Cells

Abstract

Obstructive jaundice is associated with immunologic derangements and hepatic inflammation and fibrosis. Because dendritic cells (DCs) play a major role in immune regulation, we hypothesized that the immunosuppression associated with jaundice may result from the functional impairment of liver DCs. We found that bile duct ligation (BDL) in mice expanded the myeloid subtype of liver DCs from 20 to 80% of total DCs and increased their absolute number by >15-fold. Liver myeloid DCs following BDL, but not sham laparotomy, had increased Ag uptake in vivo, high IL-6 secretion in response to LPS, and enhanced ability to activate T cells. The effects of BDL were specific to liver DCs, as spleen DCs were not affected. Expansion of liver myeloid DCs depended on Gr-1+ cells, and we implicated monocyte chemotactic protein-1 as a potential mediator. Thus, obstructive jaundice selectively expands liver myeloid DCs that are highly functional and unlikely to be involved with impaired host immune responses.

Obstructive Jaundice Expands Intrahepatic Regulatory T Cells, Which Impair Liver T Lymphocyte Function but Modulate Liver Cholestasis and Fibrosis

“…We also did not directly study the effect of BDL on other liver NPC such as DC, LSEC, and Kupffer cells. It is possible that these cell types may mediate additional effects, as we have found DC to become activated following BDL (1). There are other potential explanations for our findings that liver T cell function is altered following BDL.…”

“…Bile duct ligation (BDL) is a well-established model of obstructive jaundice (1), a condition known to alter immunity and physiology. Obstructive jaundice leads to intrahepatic inflammation and fibrosis.…”

Cholangiocyte secretion of chemokines in experimental biliary atresia

“…Increased amounts of RANTES have been found in patients with primary biliary cirrhosis, and the therapeutic benefits of fibrates in this biliary disease may be through the inhibition of this chemokine with its resultant effects on inflammatory cell migration(22). It is also thought to be a mediator of dendritic cell expansion in a murine model of obstructive jaundice(23). MCP-1 was found to be elevated in serum samples of patients with biliary atresia with liver dysfunction or portal hypertension(24).…”

Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice

“…Serum TNF-a levels were detectable at the lower limit of assay detectability and were slightly increased in BDL vs. sham mice; however, serum TNF-a levels were unchanged in T reg -depleted and nondepleted BDL mice (data not shown). The liver is a main source of circulating IL-6, and hepatic IL-6 expression is increased in BDL mice [6]. However, serum IL-6 levels were $20-fold higher in BDL compared to sham mice (p <0.01) ( Fig.…”