p120-Catenin Mediates Inflammatory Responses in the Skin

Abstract

Although p120-catenin regulates adherens junction (AJ) stability in cultured cells, genetic studies in lower eukaryotes have not revealed a role for this protein in vivo. Using conditional targeting in mice, we show that p120 null neonatal epidermis exhibits reduced intercellular AJ components but no overt disruption in barrier function or intercellular adhesion. As the mice age, however, they display epidermal hyperplasia and chronic inflammation, typified by hair degeneration and loss of body fat. Using skin engraftments and anti-inflammatory drugs, we show that these features are not attributable to reductions in junctional cadherins and catenins, but rather NFkB activation. Both in vivo and in vitro, p120 null epidermal cells activate nuclear NFkB, triggering a cascade of proinflammatory NFkB targets. Although the underlying mechanism is likely complex, we show that p120 affects NFkB activation and immune homeostasis in part through regulation of Rho GTPases. These findings provide important new insights into p120 function.

p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice

“…Second, recent evidence suggests that p120 is an important cell autonomous suppressor of inflammation (34). p120 KO in the epidermis has no discernible effect on cell-cell adhesion or barrier function, but nonetheless results in cell autonomous activation of NF-κB and a striking inflammatory response (34). Our data does not rule out such an effect in the intestines.…”

“…Whether intestinal inflammation following p120 KO is influenced by NF-κB activity, as reported previously in the epidermis (34,63), is not yet clear. p120 KD in vitro in the colon carcinoma cell line HCA7 did not increase NF-κB activity (data not shown).…”

“…In many cultured epithelial cell lines, p120 KD almost completely eliminates cell-cell adhesion (10,11), and here, we show in vivo and in vitro that p120 loss also manifests as a significant barrier defect. Second, recent evidence suggests that p120 is an important cell autonomous suppressor of inflammation (34). p120 KO in the epidermis has no discernible effect on cell-cell adhesion or barrier function, but nonetheless results in cell autonomous activation of NF-κB and a striking inflammatory response (34).…”

“…Our conditional p120 KO mouse has been used previously to target p120 ablation to the salivary gland (32) and skin (34). Here, we crossed floxed p120 mice (p120 F/F mice) to a well-characterized villin-Cre mouse model (villin-Cre) engineered to selectively express Cre in the epithelium of the intestine (35).…”

“…In striking contrast, p120 ablation in the epidermis has no discernible effect on either cell-cell adhesion or barrier function, despite similarly reduced levels of both E-and P-cadherins. Instead, these mice develop severe epidermal inflammation due to cell autonomous activation of NF-κB (34). Notably, the salivary gland (barrier defects) and epidermal (inflammation) phenotypes are major factors in the etiology of IBD.…”