Critical role of HIF-1alpha in keratinocyte defense against bacterial infection.
Skin, the first barrier against invading microorganisms, is hypoxic, even under baseline conditions. The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha, the principal regulator of cellular adaptation to low oxygen, is strongly expressed in skin epithelium. HIF-1alpha is now understood to play a key role in the bactericidal capacity of phagocytic cells such as macrophages and neutrophils. In the skin, keratinocytes provide a direct antibacterial activity through production of antimicrobial peptides, including cathelicidin. Here, we generate mice with a keratinocyte-specific deletion of HIF-1alpha and examine effects on intrinsic skin immunity. Keratinocyte HIF-1alpha is seen to provide protection against necrotic skin lesions produced by the pathogen group A Streptococcus. RNA interference studies reveal that HIF-1alpha regulation of keratinocyte cathelicidin production is critical to their antibacterial function.
Peyssonnaux
Carole
C
Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0377, USA.
Boutin
Adam T
AT
Zinkernagel
Annelies S
AS
Datta
Vivekanand
V
Nizet
Victor
V
Johnson
Randall S
RS
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000502:physiology; D015603:Keratinocytes / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013290:Streptococcal Infections / Q000276:immunology / Q000517:prevention & control*; D013297:Streptococcus pyogenes / Q000472:pathogenicity; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D054804:Cathelicidins