Implications of SM22α-Cre expression in keratinocytes and un-anticipated inflammatory skin lesions in a model of atherosclerosis

Genetically modified mice are widely used to recapitulate human diseases. Atherosclerosis can be induced in mice with low density lipoprotein receptor (Ldlr)-deficiency and high fat diet (HFD). Disintegrin and metalloproteinase-17 (ADAM17) in the smooth muscle cell (SMC) contributes to vascular pathologies, and hence its role in atherosclerosis was investigated. ADAM17 deletion in SMCs by Sm22α-Cre driver (Ldlr-/-/Adam17Sm22Cre) and HFD resulted in severe skin lesions in >70% of mice, associated with skin inflammation, which were not observed in Ldlr-/--HFD, nor in mice with SMC-deficiency of ADAM17 by a different Cre-driver (Ldlr-/-/Adam17Myh11Cre). We found that Sm22α is highly expressed in keratinocytes (compared to SMCs), which could underlie the observed skin lesion in Ldlr-/-/Adam17Sm22Cre-HFD. Although expression of Sm22α in non-SMC cells has been reported, this is the first study demonstrating a severe side-effect resulting from the off-target expression of Sm22α-Cre, resulting in ADAM17 loss in keratinocytes that led to a moribund state.