Biliary innate immunity: function and modulation

Abstract

Biliary innate immunity is involved in the pathogenesis of cholangiopathies in patients with primary biliary cirrhosis (PBC) and biliary atresia. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. In PBC, CD4-positive Th17 cells characterized by the secretion of IL-17 are implicated in the chronic inflammation of bile ducts and the presence of Th17 cells around bile ducts is causally associated with the biliary innate immune responses to PAMPs. Moreover, a negative regulator of intracellular TLR signaling, peroxisome proliferator-activated receptor-gamma (PPARgamma), is involved in the pathogenesis of cholangitis. Immunosuppression using PPARgamma ligands may help to attenuate the bile duct damage in PBC patients. In biliary atresia characterized by a progressive, inflammatory, and sclerosing cholangiopathy, dsRNA viruses are speculated to be an etiological agent and to directly induce enhanced biliary apoptosis via the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Moreover, the epithelial-mesenchymal transition (EMT) of biliary epithelial cells is also evoked by the biliary innate immune response to dsRNA.

Figure 1

Representative expression pattern of TLR4 in interlobular bile ducts. Membranous (mainly lateral) in addition to weakly cytoplasmic expression is found in Primary biliary cirrhosis. Immunohistochemistry for TLR4.

Figure 2

Immunohistochemical staining for human beta defensin (hBD)-1 (a) and hBD-2 (b). (a) Normal liver. Septal bile ducts are positive for hBD-1. (b) Extrahepatic biliary obstruction. Biliary epithelium of the intrahepatic large bile duct showing cholangitis strongly expresses hBD-2.

Figure 3

Induction of tolerance in cultured human biliary epithelial cells (BECs). BECs are pretreated with lipopolysaccharide (LPS, TLR4 ligand) or Pam₃CSK₄ (Pam3, TLR1/2 ligand) for 24 hours and subjected to another LPS challenge. Pretreatment with LPS and Pam₃CSK₄ significantly decreases NF-κB activity in response to a subsequent LPS challenge. In contrast, the pretreatment with poly (I:C) (TLR3 ligand) or LPS does not inhibit NF-κB's activation in response to a subsequent poly (I:C) challenge (* < .05).

Figure 4

IRAK-M is constitutively expressed in the cytoplasm of septal bile ducts in normal liver. Immunohistochemistry for IRAK-M.

Figure 5

Immunohistochemistry for peroxisome proliferator-activated receptor γ (PPARγ). (a) Normal liver. PPARγ is expressed in the cytoplasm of bile ducts (arrow). (b) Primary biliary cirrhosis (PBC). Damaged bile ducts (arrowhead) show reduced expression of PPARγ, though evidently positive biliary cells (arrow) also remain.

Figure 6

Effect of the peroxisome proliferator-activated receptor γ (PPARγ) ligand, 15d-PGJ2, on lipopolysaccharide (LPS, TLR4 ligand)- and peptidoglycan (PGN, TLR2 ligand)-induced NF-κB activation in cultured human biliary epithelial cells (BECs). BECs are pretreated in the presence or absence of 15d-PGJ2 (20 μM) before stimulation with LPS or peptidoglycan. Pretreatment with 15d-PGJ2 significantly prevents PAMP-induced NF-κB activation (* < .05).