Claudin-3 Loss Causes Leakage of Sweat from the Sweat Gland to Contribute to the Pathogenesis of Atopic Dermatitis

Abstract

The transfer of sweat to the skin surface without leakage is important for the homeostatic regulation of skin and is impaired in atopic dermatitis. Although the precise composition of the leakage barrier remains obscure, there is a large contribution from claudins, the major components of tight junctions. In humans, claudin-1, -3, and -15 are expressed on sweat ducts, and claudin-3 and -10 are expressed on secretory coils. Although only two claudins are expressed in murine sweat glands, we found that the expression of claudin-3 is conserved. Atopic dermatitis lesional skin had decreased claudin-3 expression in sweat glands, which was accompanied by sweat leakage. This critical role in water barrier function was confirmed in Cldn3 and Cldn3 mice and those with experimentally decreased claudin-3. Our results show the crucial role of claudin-3 in preventing sweat gland leakage and suggest that the pathogenesis of dermatoses accompanied by hypohidrosis involves abnormally decreased claudin-3.

Skin Barriers in Dermal Drug Delivery: Which Barriers Have to Be Overcome and How Can We Measure Them?

“…On the ultrastructural level, the presence of barrier-forming TJs in sweat glands of human skin has already been shown in the 1970s and 1980s [ 104 , 105 , 106 ]. Sweat glands express occludin, claudin-1, claudin-3, claudin-4, claudin-10b and claudin-15 as well as ZO-1 and ZO-2 in human skin with varying expression patterns depending on the localization within the gland [ 107 , 108 , 109 ]. Claudin-1 is often absent from the barrier-forming TJs, while claudin-3, claudin-10 and claudin-15 seem to be more prominent.…”

“…Claudin-1 is often absent from the barrier-forming TJs, while claudin-3, claudin-10 and claudin-15 seem to be more prominent. Of note, in mouse skin, only claudin-3, claudin-4 and claudin-10 are present [ 109 ].…”

“…Claudin-3 knock-out mice show TJ leakage and—putatively due to decreased retention of the sweat in the lumen of the upper sweat gland—less sweat [ 109 ]. Humans with less claudin-10b in sweat glands due to a missense mutation in the CLDN10B gene, exhibit anhidrosis.…”

“…Related experiments in 3D cultures modelling sweat secretion showed that an impaired TJ strand formation perturbs paracellular sodium transport [ 108 ]. Patients with AD show decreased sweat volume and decreased expression of claudin-1, claudin-3, and claudin-15 [ 109 ].…”

Tight Junction barriers in human hair follicles – role of claudin-1

“…Because we have shown here that TJs also form a barrier in human HFs and therefore contribute to overall barrier function of the skin we wanted to check whether Cldn-1 is also affected in HFs of lesional or non-lesional skin from AD patients compared to healthy control skin. In addition, it was recently shown that Cldn-1 is also down-regulated in sweat glands of lesional AD skin 38 .…”