Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris

Abstract

The severe autoimmune blistering disease Pemphigus vulgaris (PV) is mainly caused by autoantibodies (IgG) against desmoglein (Dsg) 3 and Dsg1. The mechanisms leading to the development of blisters are not fully understood, but intracellular signaling seems to play an important role. Sheddases ADAM10 and ADAM17 are involved in the turnover of the desmosomal cadherin Dsg2 and ADAM10 has been shown to contribute to acantholysis in a murine pemphigus model. In the present study, we further examined the role of ADAM10 and ADAM17 both in keratinocyte adhesion and in the pathogenesis of PV. First, we found that inhibition of ADAM10 enhanced adhesion of primary human keratinocytes but not of immortalized keratinocytes. In dissociation assays, inhibition of ADAM10 shifted keratinocyte adhesion towards a hyperadhesive state. However, ADAM inhibition did neither modulate protein levels of Dsg1 and Dsg3 nor activation of EGFR at Y1068 and Y845. In primary human keratinocytes, inhibition of ADAM10, but not ADAM17, reduced loss of cell adhesion and fragmentation of Dsg1 and Dsg3 immunostaining in response to a PV1-IgG from a mucocutaneous PV patient. Similarly, inhibition of ADAM10 in dissociation assay decreased fragmentation of primary keratinocytes induced by a monoclonal antibody against Dsg3 and by PV-IgG from two other patients both suffering from mucosal PV. However, such protective effect was not observed in both cultured cells and ex vivo disease models, when another mucocutaneous PV4-IgG containing more Dsg1 autoantibodies was used. Taken together, ADAM10 modulates both hyperadhesion and PV-IgG-induced loss of cell adhesion dependent on the autoantibody profile.

Cardiomyocyte cohesion is increased after ADAM17 inhibition

“…Nevertheless, EGFR signaling was not affected by TAPI-1 treatment, suggesting that EGFR might not be involved in ADAM17 inhibition-mediated positive adhesiotropy. A recent study in keratinocytes also revealed that ADAM17 inhibition did not alter EGFR signaling ( Kugelmann et al, 2022 ). In mice lacking DSG2, ADAM17 was increased in 2 week old hearts ( Ng et al, 2021 ).…”

New insights into the function and pathophysiology of the ectodomain sheddase A Disintegrin And Metalloproteinase 10 (ADAM10)

“…In cell‐based assays, the inhibition of ADAM10 exerts protective effects by preventing the autoantibody‐induced loss of intercellular adhesion in human keratinocytes. These results were limited to certain autoantibody profiles (antibodies against Dsg1 and Dsg3, but not Dsc3) and do not seem to hold true for every subtype of the disease [110]. ADAM10 is also involved in the direct regulation of Dsg2 turnover since it cleaves the desmosomal protein [111] (Fig.…”

“…Altogether, high Dsg3 and low Dsg1 autoantibody levels constitute a constellation where an inhibition of ADAM10 might be a favorable intervention to decelerate PV progression, even though there is still a lack of in vivo or even clinical data. Other autoantibody profiles have presented themselves as nonresponsive to ADAM10 inhibition [110].…”

cAMP: A master regulator of cadherin‐mediated binding in endothelium, epithelium and myocardium

“…224,225 Interestingly, signaling traits regulating cell adhesion are shared in different desmosome-related diseases. 14 Since signaling by p38MAPK and EGFR have been found to be upregulated in models of both pemphigus and arrhythmogenic cardiomyopathy and ADAM17 was found to regulate desmosomal adhesion in keratinocytes in pemphigus and also in cardiomyocytes, 214,[242][243][244] it is possible that cAMP signaling may also serve as a possible target in other desmosome-related diseases. In addition, cAMP signaling may be employed to regulate the behavior of other cells.…”