Implications of -Cre expression in keratinocytes and unanticipated inflammatory skin lesion 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 ()-deficiency and a high-fat diet (HFD). Disintegrin and metalloproteinase-17 (ADAM17) in the smooth muscle cell (SMC) contribute to vascular pathologies, and hence its role in atherosclerosis was investigated. deletion in SMCs by -Cre driver (/) and HFD resulted in severe skin lesions in >70% of mice, associated with skin inflammation, which was not observed in -HFD, nor in mice with SMC deficiency of by a different Cre driver (/). We found that is highly expressed in keratinocytes (compared with SMCs), which could underlie the observed skin lesion in /-HFD. Although expression of in non-SMCs has been reported, this is the first study demonstrating a severe side effect resulting from the off-target expression of -Cre, resulting in ADAM17 loss in keratinocytes that led to a moribund state. Although -Cre is commonly used to target gene deletion in smooth muscle cells, -derived deletion resulted in unexpected severe skin lesions following high-fat diet feeding in a model of atherosclerosis. deletion by a different SMC driver, -Cre, did not result in skin lesions in the same atherosclerosis model. is highly expressed in keratinocytes, causing ectopic loss of ADAM17 in keratinocytes that caused significant epidermal lesions when combined with a high-fat diet.