Roles of infection, inflammation, and the immune system in cholesterol gallstone formation

Abstract

Cholesterol gallstone formation is a complex process mediated by genetic and environmental factors. Until recently, the role of the immune system in the pathogenesis of cholesterol gallstones was not considered a valid topic of research interest. This review collates and interprets an extensive body of basic literature, some of which is not customarily considered to be related to cholelithogenesis, describing the multiple facets of the immune system that appear to be involved in cholesterol cholelithogenesis. A thorough understanding of the immune interactions with biliary lipids and cholecystocytes should modify current views of the pathogenesis of cholesterol gallstones, promote further research on the pathways involved, and lead to novel diagnostic tools, treatments, and preventive measures.

Figure 1

The physical-chemical processes involved in formation of cholesterol gallstones. The classic physical-chemical symbols for cholesterol (pink), phospholipid (green), and bile salt (purple) molecules are shown, along with the macromolecular structures they form. Cholesterol, phospholipids, and bile salts combine by hydrophobic interactions to form mixed micelles (micelles) and cholesterol and phospholipids form unilamellar vesicles. Normally the unilamellar vesicles would be ∼5–10 times larger than micelles (∼40 Å in radius), but for illustration purposes they are depicted here nonproportionately. As cholesterol concentration in gallbladder bile increases principally from hepatic hypersecretion of cholesterol, the true supersaturated state forms transiently. Supersaturated bile usually implies that phase separation of excess cholesterol from micelles has occurred, forming unilamellar vesicles with biliary phospholipids (mostly >95% phosphatidylcholine). In the most common nucleation sequence, unilamellar vesicles fuse to form multilamellar vesicles, or liquid crystals, which are visible by low-power polarizing microscopy. From these, plate-like cholesterol monohydrate crystals (solid cholesterol crystals) nucleate heterogeneously, usually in a mucin gel. The dotted arrow indicates how cholesterol can occasionally phase separate directly from supersaturated micelles. The solid resulting cholesterol monohydrate crystals are a polymorph of the classic cholesterol monohydrate plates into which they transform with passage of time. Once the nucleation sequence has occurred and solid cholesterol crystals have formed, the phase sequence is not repeated if bile remains continuously supersaturated. Gallbladder dysmotility and mucin gel formation also contribute to the aggregation of the plate-like cholesterol monohydrate crystals and contribute to their agglomeration and growth into macroscopic cholesterol gallstones.

Figure 2

Receptors and ligands expressed by biliary epithelial cells. The receptors (displayed on the basolateral surface of the cell) and ligands (displayed extracellularly) expressed by biliary epithelial cells are shown in the unstimulated (right panel) and stimulated (left panel) state. The receptors, ligands, and cells that interact with these biliary expressed proteins are also shown. CCL, chemokine CC motif ligand; CCR, chemokine CC motif receptor; CXCL, chemokine CXC ligand; CXCR, chemokine CXC receptor; LFA, lymphocyte function-associated antigen; MHC, major histocompatibility complex.

Figure 3

Immune system–stimulated production of MUC2. Various pathogen-associated molecular patterns (PAMPs), through their interaction with TLR molecules, increase the production of mucin 2 (MUC2). A portion of this increase seems to be due to increased production of caudal type homeobox transcription factor 2 (CDX2), which feeds back to stimulate MUC2 production. Further, LPS and TNF-α stimulate the production of MUC2. In the case of LPS, this stimulation seems to be mediated through the TNF-α pathway because inhibition of TNF-α blocks the effects of LPS treatment on MUC2 production.

Figure 4

The points at which the immune system stimulates production of MUC5AC. As described for mucin 2, LPS stimulation leads to production of mucin 5AC (MUC5AC) in a TNF-α dependent manner (not shown). TNF-α acts via protein kinase C (PKC)-dependent and EGF-mediated pathways to up-regulate MUC5AC production. In the case of the EGF pathway, this up-regulation results from the production of apical EGF receptors and subsequent binding to apical EGF.

Figure 5

Stimulation of mucin 3 (MUC3) production by LPS via CD14 and likely TLR molecules. Stimulation of MUC3 by LPS is independent of TNF-α, in contrast to MUC2 and MUC5AC. It is currently unclear what downstream pathways are important in LPS stimulation of MUC3 production.