Individual claudin proteins are generally classified as either barrier-forming or pore-forming (channel-forming) claudins, depending on whether their expression increases or decreases permeability. For example, overexpression of claudin-1 and 4 in MDCK epithelial cells leads to decreased permeability (Van Itallie C et al. 2001).
A reduction in claudin-1 expression in human skin keratinocytes leads to increased epithelial permeability, indicating a disruption of barrier function (Yamamoto T et al. 2008; De Benedetto A et al. 2011). Therefore, claudin-1 and claudin-4 are classified as barrier claudins. Other barrier claudins are claudins 5, 6, 8, 9, 11, 15 and 19. Overexpression of claudin-6 also downregulates the expression of other claudins, suggesting a negative feedback loop between existing claudins and subsequent claudin expression.
Claudin-4, for example, is a prototypic barrier-forming claudin that reduces paracellular permeability by a previously unknown mechanism. Claudin-4 selectively inhibits flux through cation channels formed by claudins 2 or 15. Claudin-4-induced loss of claudin channel function is associated with reduced anchoring and subsequent endocytosis of pore-forming claudins. Analyses in non-epithelial cells show that although claudin-4 is not capable of independent polymerization, it destroys polymer strands and higher-order networks formed by claudins 2, 7, 15 and 19. This process of interclaudin interference, in which one claudin destroys higher-order structures and channels formed by another claudin, represents a previously unknown mechanism of barrier regulation (Shashikanth N et al. 2022).
In claudin-6 overexpressing mice, the epidermis also shows abnormal expression of differentiation markers such as keratin 1, filaggrin, loricrin and involucrin (Turksen K et al. 2002).
Interleukin-33 reduces the expression of filaggrin and claudin-1, which leads to a reduction in the barrier function of the skin. However, the destruction of the barrier leads to percutaneous exposure to allergens or the release of interleukin-33 (IL-33). Thus, IL-33 is a common target for the itch-scratch cycle of atopic dermatitis (Imai Y 2019). Remarkably, filaggrin gene knockdown leads to a reduced level not only of keratin 10 but also of the TJ proteins ZO-1, claudin-1 and occludin. In parallel, there is an increase in cysteine proteases, which in turn can degrade TJ proteins (Wang et al. 2017).
In addition to their functions and expression in epithelial tissues, claudins have also been identified in tissue-specific distributions in the endothelium. For example, human brain and mouse endothelial cells express claudins 3, 5 and 12, while kidney endothelial cells express claudins 5 and 15.