A mouse model for vitamin D-induced human cathelicidin antimicrobial peptide gene expression
A mouse model for vitamin D-induced human cathelicidin antimicrobial peptide gene expression
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DOI：
10.1016/j.jsbmb.2019.105552
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发表时间：
2020-04-01
影响因子：
4.1
通讯作者：
Gombart, Adrian F.
中科院分区：
文献类型：
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作者：
Lowry, Malcolm B.;Guo, Chunxiao;Gombart, Adrian F.
在人类和其他灵长类动物中，1,25(OH)(2)维生素D-3通过激活维生素D通路的toll样受体（TLR）信号调节抗菌肽（CAMP）基因的表达。小鼠和其他哺乳动物的CAMP启动子中缺乏维生素D反应元件（VDRE）。为了阐明这一途径的生物学重要性，我们培育了携带包含整个人类CAMP基因的基因组DNA片段的转基因小鼠，并将它们与CAMP敲除（KO）小鼠杂交。我们观察到人基因在多种组织和先天免疫细胞中的表达。然而，在小鼠CAMP转基因巨噬细胞中，TLR在25(OH)D-3存在下的激活不会诱导CAMP或CYP27B1的表达，而在人类巨噬细胞中通常会发生这种情况，这加强了维生素d作用的重要物种差异。转基因小鼠确实对鼠伤寒沙门氏菌在肠道中的定植表现出增强的抗性。此外，人类CAMP基因恢复了CAMP KO小鼠皮肤的伤口愈合。在伤口感染模型中，将1,25(OH)(2)维生素D-3局部应用于CAMP转基因小鼠皮肤可诱导CAMP表达并增加金黄色葡萄球菌的杀伤。我们的模型可以帮助阐明维生素D-cathelicidin通路在致病性和非致病性状态下的生物学重要性。
In humans and other primates, 1,25(OH)(2)vitamin D-3 regulates the expression of the cathelicidin antimicrobial peptide (CAMP) gene via toll-like receptor (TLR) signaling that activates the vitamin D pathway. Mice and other mammals lack the vitamin D response element (VDRE) in their CAMP promoters. To elucidate the biological importance of this pathway, we generated transgenic mice that carry a genomic DNA fragment encompassing the entire human CAMP gene and crossed them with Camp knockout (KO) mice. We observed expression of the human transgene in various tissues and innate immune cells. However, in mouse CAMP transgenic macrophages, TLR activation in the presence of 25(OH)D-3 did not induce expression of either CAMP or CYP27B1 as would normally occur in human macrophages, reinforcing important species differences in the actions of vitamin D. Transgenic mice did show increased resistance to colonization by Salmonella typhimurium in the gut. Furthermore, the human CAMP gene restored wound healing in the skin of Camp KO mice. Topical application of 1,25(OH)(2)vitamin D-3 to the skin of CAMP transgenic mice induced CAMP expression and increased killing of Staphylococcus aureus in a wound infection model. Our model can help elucidate the biological importance of the vitamin D-cathelicidin pathway in both pathogenic and non-pathogenic states.