A toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria.
flake (flk), an N-ethyl-N-nitrosourea-induced recessive germ line mutation of C57BL/6 mice, impairs the clearance of skin infections by Streptococcus pyogenes and Staphylococcus aureus, gram-positive pathogens that elicit innate immune responses by activating Toll-like receptor 2 (TLR2). Positional cloning and sequencing revealed that flk is a novel allele of the stearoyl coenzyme A desaturase 1 gene (Scd1). flake homozygotes show reduced sebum production and are unable to synthesize the monounsaturated fatty acids (MUFA) palmitoleate (C(16:1)) and oleate (C(18:1)), both of which are bactericidal against gram-positive (but not gram-negative) organisms in vitro. However, intradermal MUFA administration to S. aureus-infected mice partially rescues the flake phenotype, which indicates that an additional component of the sebum may be required to improve bacterial clearance. In normal mice, transcription of Scd1-a gene with numerous NF-kappaB elements in its promoter--is strongly and specifically induced by TLR2 signaling. Similarly, the SCD1 gene is induced by TLR2 signaling in a human sebocyte cell line. These observations reveal the existence of a regulated, lipid-based antimicrobial effector pathway in mammals and suggest new approaches to the treatment or prevention of infections with gram-positive bacteria.
Georgel
Philippe
P
Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Crozat
Karine
K
Lauth
Xavier
X
Makrantonaki
Evgenia
E
Seltmann
Holger
H
Sovath
Sosathya
S
Hoebe
Kasper
K
Du
Xin
X
Rutschmann
Sophie
S
Jiang
Zhengfan
Z
Bigby
Timothy
T
Nizet
Victor
V
Zouboulis
Christos C
CC
Beutler
Bruce
B
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002874:Chromosome Mapping; D005128:Eye Diseases / Q000382:microbiology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D016013:Likelihood Functions; D008126:Lod Score; D051379:Mice; D008810:Mice, Inbred C57BL; D019301:Oleic Acid / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D013207:Staphylococcal Skin Infections / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics* / Q000378:metabolism; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D051195:Toll-Like Receptor 2
D000900:Anti-Bacterial Agents; D005229:Fatty Acids, Monounsaturated; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C008757:palmitoleic acid; D019301:Oleic Acid; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase