A mouse model for vitamin D-induced human cathelicidin antimicrobial peptide gene expression

Malcolm B. Lowry, Chunxiao Guo, Yang Zhang, Mary L. Fantacone, Isabelle E. Logan, Yan Campbell, Weijian Zhang, Mai Le, Arup K. Indra, Gitali Ganguli-Indra, Jingwei Xie, Richard L. Gallo, H. Phillip Koeffler, Adrian F. Gombart

Research output: Contribution to journalArticle

Abstract

In humans and other primates, 1,25(OH)2vitamin D3 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)D3 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)2vitamin D3 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.

Original languageEnglish (US)
Article number105552
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume198
DOIs
StatePublished - Apr 2020

Fingerprint

Gene expression
Vitamin D
Gene Expression
Transgenic Mice
Genes
Macrophages
Toll-Like Receptors
Knockout Mice
Skin
Vitamin D Response Element
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Salmonella
Mammals
cathelicidin antimicrobial peptide
Wound Infection
Salmonella typhimurium
Transgenes
Wound Healing
Primates
Staphylococcus aureus

Keywords

  • Cathelicidin
  • Cyp27b1
  • Innate immunity
  • Macrophage
  • TLR
  • Vitamin D

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Lowry, M. B., Guo, C., Zhang, Y., Fantacone, M. L., Logan, I. E., Campbell, Y., ... Gombart, A. F. (2020). A mouse model for vitamin D-induced human cathelicidin antimicrobial peptide gene expression. Journal of Steroid Biochemistry and Molecular Biology, 198, [105552]. https://doi.org/10.1016/j.jsbmb.2019.105552

A mouse model for vitamin D-induced human cathelicidin antimicrobial peptide gene expression. / Lowry, Malcolm B.; Guo, Chunxiao; Zhang, Yang; Fantacone, Mary L.; Logan, Isabelle E.; Campbell, Yan; Zhang, Weijian; Le, Mai; Indra, Arup K.; Ganguli-Indra, Gitali; Xie, Jingwei; Gallo, Richard L.; Koeffler, H. Phillip; Gombart, Adrian F.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 198, 105552, 04.2020.

Research output: Contribution to journalArticle

Lowry, MB, Guo, C, Zhang, Y, Fantacone, ML, Logan, IE, Campbell, Y, Zhang, W, Le, M, Indra, AK, Ganguli-Indra, G, Xie, J, Gallo, RL, Koeffler, HP & Gombart, AF 2020, 'A mouse model for vitamin D-induced human cathelicidin antimicrobial peptide gene expression', Journal of Steroid Biochemistry and Molecular Biology, vol. 198, 105552. https://doi.org/10.1016/j.jsbmb.2019.105552
Lowry, Malcolm B. ; Guo, Chunxiao ; Zhang, Yang ; Fantacone, Mary L. ; Logan, Isabelle E. ; Campbell, Yan ; Zhang, Weijian ; Le, Mai ; Indra, Arup K. ; Ganguli-Indra, Gitali ; Xie, Jingwei ; Gallo, Richard L. ; Koeffler, H. Phillip ; Gombart, Adrian F. / A mouse model for vitamin D-induced human cathelicidin antimicrobial peptide gene expression. In: Journal of Steroid Biochemistry and Molecular Biology. 2020 ; Vol. 198.
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abstract = "In humans and other primates, 1,25(OH)2vitamin D3 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)D3 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)2vitamin D3 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.",
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