1. ¹Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA
2. ²Department of Pediatrics, University of California, San Diego, La Jolla, California, USA

Correspondence: Dr Randall S. Johnson, Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, MC 0377, La Jolla, California 92093-0377, USA. E-mail: rsjohnson@ucsd.edu

Received 14 November 2006; Revised 20 August 2007; Accepted 26 September 2007; Published online 6 March 2008.

Abstract

Skin, the first barrier against invading microorganisms, is hypoxic, even under baseline conditions. The transcription factor hypoxia-inducible factor-1 (HIF-1, the principal regulator of cellular adaptation to low oxygen, is strongly expressed in skin epithelium. HIF-1 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-1 and examine effects on intrinsic skin immunity. Keratinocyte HIF-1 is seen to provide protection against necrotic skin lesions produced by the pathogen group A Streptococcus. RNA interference studies reveal that HIF-1 regulation of keratinocyte cathelicidin production is critical to their antibacterial function.