Abstract
Previously reported abnormalities in the reproductive-tract of female adipose-tissue-specific (ap2-Cre) ERα-knockout (ERaKO)-mice were linked with a 40% decrease of ERα-gene-expression in the hypothalamus of these animals, when compared to their control-mice (ERα-floxed;WT). Subsequently, ERaKO-mice showed a pronounced upregulation of estradiol (E2)-plasma levels (KO: 45.9 vs. WT: 19.8pg/ml;p < 0.01) resulting from diminished ERα-mediated feedback in the hypothalamus. When fed with high-fat-diet (HFD), KO-mice developed a pronounced inflammation of uteri. To investigate the cause underlying this inflammatory process we performed H&E-, cd3-, Mac387- and Ly6G-stainings, a semiquantitative scoring of the inflammatory grade and microbiological analysis of the uteri. As HFD-feeding seems to accelerate the inflammatory response in those mice, we also analysed the plasma fatty-acid-profile of the ERaKO-mice fed with a normal-chow-diet (NCD) and HFD. We identified a massive accumulation of neutrophils in the uterus wall, while macrophages and lymphocytes were rarely present. The grade of inflammation (scored from 0 = no inflammation to 3 = most severe form) in HFD-fed KO-mice was significantly higher than in NCD-fed KO-mice (HFD: 2.44 vs. NCD: 1.76 arbitrary units). In accordance, we found that HFD-feeding resulted in increased stearic (c18:0; 983 vs. 567 µg/ml;p < 0.001) and arachidonic (c20:4 n-6; 976 vs. 594 µg/ml;p < 0,001) acid-levels in plasma. Moreover, PCR-analysis of bacterial DNA identified E. coli and Enterococcus sp. as main pathogenic bacteria present in tissue and uterine-fluid of ERaKO-mice. Taken together, our data suggest that high E2-levels in combination with a dysregulated fatty-acid-plasma profile modulate the immune-response of neutrophils and/or macrophages to bacterial infections, resulting in the inability of terminating the inflammatory process.
Published Version
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