Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infection.
Inflammatory caspases are important effectors of innate immunity. Caspase-12, of the inflammatory caspase subfamily, is expressed in all mammals tested to date, but has acquired deleterious mutation in humans. A single-nucleotide polymorphism introduces a premature stop codon in caspase-12 in the majority of the population. However, in 20% of African descendants, caspase-12 is expressed and sensitizes to infections and sepsis. Here, we examined the modalities by which human caspase-12 confers susceptibility to infection. We have generated a fully humanized mouse that expresses the human caspase-12 rare variant (Csp-12L) in a mouse casp-12(-/-) background. Characterization of the humanized mouse uncovered sex differences in Csp-12L expression and gender disparity in innate immunity to Listeria monocytogenes infection. The Csp-12L transgene completely reversed the knockout resistance-to-infection phenotype in casp-12(-/-) males. In contrast, it had a marginal effect on the response of female mice. We found that estrogen levels modulated the expression of caspase-12. Csp-12L was expressed in male mice but its expression was repressed in female mice. Administration of 17-beta-estradiol (E2) to humanized male mice had a direct suppressive effect on Csp-12L expression and conferred relative resistance to infection. Chromatin immunoprecipitation experiments revealed that caspase-12 is a direct transcriptional target of the estrogen receptor alpha (ERalpha) and mapped the estrogen response element (ERE) to intron 7 of the gene. We propose that estrogen-mediated inhibition of Csp-12L expression is a built-in mechanism that has evolved to protect females from infection.
Yeretssian
Garabet
G
Department of Medicine, Centre for the Study of Host Resistance and Complex Trait Group, McGill University, Montreal, QC, Canada H3G 0B1.
Doiron
Karine
K
Shao
Wei
W
Leavitt
Blair R
BR
Hayden
Michael R
MR
Nicholson
Donald W
DW
Saleh
Maya
M
D000818:Animals; D053454:Caspase 12 / Q000235:genetics*; D061945:Caspase Inhibitors; D047369:Chromatin Immunoprecipitation; D018389:Codon, Nonsense / Q000235:genetics; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020871:RNA Stability / Q000235:genetics; D012737:Sex Factors
D061945:Caspase Inhibitors; D018389:Codon, Nonsense; D047628:Estrogen Receptor alpha; D004958:Estradiol; D053454:Caspase 12