fig7

Figure 7. A hypothesis on the pathophysiology of PSC. PC in mucus originates from systemic sources. Within a lipoprotein-free fraction, PC travels out of the capillaries through endothelial gaps and distributes in the interstitial spaces between cholangiocytes, into which PC cannot enter due to its complex structure. With its positively charged head group, PC is drawn to the negatively charged TJ. Over time, PC accumulates and passes through the protein strands of the TJ to the outer surface of cholangiocytes driven by the negative charge generated by CFTR and AE2. PC then binds to mucin 3, which is anchored in the external plasma membrane, before being transferred to secretory mucin 2 to move further distally within the mucus of the biliary channel system. In cases of TJ disease, the attraction to TJ proteins fails, preventing the outward movement of PC. Any disruption in the complex PC secretion mechanism, particularly the binding to the TJ, can lead to insufficient PC accumulation in biliary mucus. This lack of mucus hydrophobicity results in a defective mucus barrier, allowing bile acids from the biliary lumen to harm cholangiocytes. This leads to an inflammatory response (cholangitis) and activates repair mechanisms like fibrosis, as is typical of PSC. Ultimately, this allows for bacterial invasion and the progression of the disease^[43,46]. This image was modified from^[38]. PC: Phosphatidylcholine; PSC: primary sclerosing cholangitis; TJ: tight junction; CFTR: cystic fibrosis transmembrane conductance regulator; AE2: anion exchange protein 2.