Claudin 4 knockout mice: normal physiological phenotype with increased susceptibility to lung injury

Abstract

Claudins are tight junction proteins that regulate paracellular ion permeability of epithelium and endothelium. Claudin 4 has been reported to function as a paracellular sodium barrier and is one of three major claudins expressed in lung alveolar epithelial cells (AEC). To directly assess the role of claudin 4 in regulation of alveolar epithelial barrier function and fluid homeostasis in vivo, we generated claudin 4 knockout (Cldn4 KO) mice. Unexpectedly, Cldn4 KO mice exhibited normal physiological phenotype although increased permeability to 5-carboxyfluorescein and decreased alveolar fluid clearance were noted. Cldn4 KO AEC monolayers exhibited unchanged ion permeability, higher solute permeability, and lower short-circuit current compared with monolayers from wild-type mice. Claudin 3 and 18 expression was similar between wild-type and Cldn4 KO alveolar epithelial type II cells. In response to either ventilator-induced lung injury or hyperoxia, claudin 4 expression was markedly upregulated in wild-type mice, whereas Cldn4 KO mice showed greater degrees of lung injury. RNA sequencing, in conjunction with differential expression and upstream analysis after ventilator-induced lung injury, suggested Egr1, Tnf, and Il1b as potential mediators of increased lung injury in Cldn4 KO mice. These results demonstrate that claudin 4 has little effect on normal lung physiology but may function to protect against acute lung injury.

Astrocytic tight junctions control inflammatory CNS lesion pathogenesis

“…Previous studies have shown that constitutive Cldn1 inactivation in mice results in perinatal death due to loss of epidermal TJ integrity (23), while CLDN4 is also expressed in kidney and lung, and constitutive or conditional Cldn4 inactivation has been linked to urothelial hyperplasia and hydronephrosis (53), failure of chloride reabsorption (54), and susceptibility to lung injury (33). Our results thus suggest that the BBB and GL represent a coordinated double barrier to CNS entry.…”

The relative balance of GM-CSF and TGF-β1 regulates lung epithelial barrier function

“…Our data suggest that retention of claudin-4 alone is not sufficient to support normal lung epithelial barrier function. Consistent with this observation, claudin-4-deficient mice have a relatively mild lung phenotype (23). Moreover, claudin-4 upregulation does not rescue the decrease in AEC barrier function found in claudin-18 knockout mice (31,32).…”

Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions

“…Within the alveolus, claudin-4 is expressed by both type I and type II pneumocytes [38]. The importance of claudin-4 in lung function is demonstrated by the fact that claudin-4 knockout mice display increased permeability to 5-carboxyfluorescein and decreased alveolar fluid clearance [39]. In vitro, the transduction of cells with claudin-4 increased the TER by ∼50% [40].…”