Identification of novel genes that mediate innate immunity using inbred mice.
Innate immunity is the first line of defense against microbial infections. Although polymorphisms in toll-like receptors (TLRs) and downstream signaling molecules (CD14, TLR2, TLR4, TLR5, and IRAK4) affect the innate immune response, these variants account for only a portion of the ability of the host to respond to bacteria, fungi, and viruses. To identify other genes involved in the innate immune response, we challenged 16 inbred murine strains with lipopolysaccharide (LPS) systemically and measured serum concentrations of pro-inflammatory cytokines IL-1beta, IL-6, and TNFalpha, and the chemokine KC 6 hr post-treatment. Loci that segregate with strain phenotypes were identified by whole genome association (WGA) mapping of cytokine concentrations. Published gene expression profiles and quantitative trait loci (QTL) were then utilized to prioritize loci and genes that potentially regulate the host response to LPS. Sixteen loci were selected for further investigation by combining WGA analysis with previously published QTL for murine response to LPS or gram negative bacteria. Thirty-eight genes within these loci were then selected for further investigation on the basis of the significance of the identified locus, transcriptional response to LPS, and biological plausibility. RNA interference-mediated inhibition of 4 of 38 candidate genes was shown to block the production of IL-6 in J774A.1 macrophages. In summary, our analysis identified 4 genes that have not previously been implicated in innate immunity, namely, 1110058L19Rik, 4933415F23Rik, Fbxo9, and Ipo7. These genes could represent potential sepsis biomarkers or therapeutic targets that should be further investigated in human populations.
Yang
Ivana V
IV
Department of Medicine, National Jewish Health, Denver, Colorado 80206, USA. yangi@njhealth.org
Wade
Claire M
CM
Kang
Hyun Min
HM
Alper
Scott
S
Rutledge
Holly
H
Lackford
Brad
B
Eskin
Eleazar
E
Daly
Mark J
MJ
Schwartz
David A
DA
D000818:Animals; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000097:blood; D002874:Chromosome Mapping; D019295:Computational Biology; D056426:Genetic Loci / Q000235:genetics; D055106:Genome-Wide Association Study; D007113:Immunity, Innate / Q000235:genetics*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D034622:RNA Interference
D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D008070:Lipopolysaccharides