title: Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism.
abstract: An essential element of the innate immune response to injury is the capacity to recognize microbial invasion and stimulate production of antimicrobial peptides. We investigated how this process is controlled in the epidermis. Keratinocytes surrounding a wound increased expression of the genes coding for the microbial pattern recognition receptors CD14 and TLR2, complementing an increase in cathelicidin antimicrobial peptide expression. These genes were induced by 1,25(OH)2 vitamin D3 (1,25D3; its active form), suggesting a role for vitamin D3 in this process. How 1,25D3 could participate in the injury response was explained by findings that the levels of CYP27B1, which converts 25OH vitamin D3 (25D3) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-beta1. Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-beta1 from inducing cathelicidin, CD14, or TLR2 in human keratinocytes, while CYP27B1-deficient mice failed to increase CD14 expression following wounding. The functional consequence of these observations was confirmed by demonstrating that 1,25D3 enabled keratinocytes to recognize microbial components through TLR2 and respond by cathelicidin production. Thus, we demonstrate what we believe to be a previously unexpected role for vitamin D3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.
authors.affiliation: Division of Dermatology, University of California, San Diego, and VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schauber
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dorschner
authors.forename: Alvin B
authors.initials: AB
authors.lastname: Coda
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Büchau
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: Kiken
authors.forename: Yolanda R
authors.initials: YR
authors.lastname: Helfrich
authors.forename: Sewon
authors.initials: S
authors.lastname: Kang
authors.forename: Hashem Z
authors.initials: HZ
authors.lastname: Elalieh
authors.forename: Andreas
authors.initials: A
authors.lastname: Steinmeyer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zügel
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000737:chemistry / Q000276:immunology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D015603:Keratinocytes / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors; D051195:Toll-Like Receptor 2 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014807:Vitamin D / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D018950:Lipopolysaccharide Receptors; D018167:Receptors, Calcitriol; D051195:Toll-Like Receptor 2; D053773:Transforming Growth Factor beta1; D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D054804:Cathelicidins