Implications of Sm22α -Cre expression in keratinocytes and unanticipated inflammatory skin lesion in a model of atherosclerosis

• Published in: American journal of physiology. Heart and circulatory physiology 2022-09, Vol.323 (3), p.H528-H534
• Main Authors: Hu, Mei, Hiroyasu, Sho, Granville, David J., Kassiri, Zamaneh
• Format: Article
• Language: English
• Subjects: Arteriosclerosis; Atherosclerosis; Genetic modification; High fat diet; Inflammation; Keratinocytes; Lesions; Low density lipoprotein receptors; Muscles; Receptor density; Skin diseases; Skin lesions; Smooth muscle
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00325.2022

Although Sm22α-Cre is commonly used to target gene deletion in smooth muscle cells, Sm22α-derived Adam17 deletion resulted in unexpected severe skin lesions following high-fat diet feeding in a model of atherosclerosis. Adam17 deletion by a different SMC driver, Myh11-Cre, did not result in skin lesions in the same atherosclerosis model. Sm22α is highly expressed in keratinocytes, causing ectopic loss of ADAM17 in keratinocytes that caused significant epidermal lesions when combined with a high-fat diet. Genetically modified mice are widely used to recapitulate human diseases. Atherosclerosis can be induced in mice with low-density lipoprotein receptor ( Ldlr)-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. Adam17 deletion in SMCs by Sm22α-Cre driver ( Ldlr −/− / Adam17 Sm22Cre ) and HFD resulted in severe skin lesions in >70% of mice, associated with skin inflammation, which was not observed in Ldlr −/− -HFD, nor in mice with SMC deficiency of Adam17 by a different Cre driver ( Ldlr −/− / Adam17 Myh11 Cre ). We found that Sm22α is highly expressed in keratinocytes (compared with SMCs), which could underlie the observed skin lesion in Ldlr −/− / Adam17 Sm22Cre -HFD. Although expression of Sm22α in non-SMCs 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. NEW & NOTEWORTHY Although Sm22α-Cre is commonly used to target gene deletion in smooth muscle cells, Sm22α-derived Adam17 deletion resulted in unexpected severe skin lesions following high-fat diet feeding in a model of atherosclerosis. Adam17 deletion by a different SMC driver, Myh11-Cre, did not result in skin lesions in the same atherosclerosis model. Sm22α is highly expressed in keratinocytes, causing ectopic loss of ADAM17 in keratinocytes that caused significant epidermal lesions when combined with a high-fat diet. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/sm22alpha-in-keratinocytes/ .