fig1

Figure 1. A hypothesis on the pathophysiology of mucosal diseases due to disturbed TJs. PC in mucus originates from systemic sources. In a LPFF, PC leaves capillaries through endothelial gaps and moves into the interstitial spaces between mucosal cells. Due to its complex structure, PC cannot enter the mucosal cells themselves. With its positively charged head group, PC is attracted to the negatively charged TJs. Over time, PC accumulates and passes through the protein strands of the TJ to the outer surface of the mucosal cells, driven by the negative charge generated by the CFTR and the AE2. Extracellular PC arranges itself in the mucus as a bilayer, with the positively charged choline head group attached to negatively charged mucin. First PC binds to membrane-anchored mucins before transferring to secretory mucins to continue its movement distally within the mucosa system. In cases of TJ disease, PC translocation to the mucus layer fails. The resulting lack of mucus PC leads to a defective mucus barrier, allowing luminal pathogens to enter. This image was made with CorelDRAW. TJs: Tight junctions; PC: phosphatidylcholine; LPFF: lipoprotein-free fraction; CFTR: cystic fibrosis transmembrane conductance regulator; AE2: anion exchange protein 2.