TY - JOUR
T1 - Sex-opposed inflammatory effects of 27-hydroxycholesterol are mediated via differences in estrogen signaling
AU - Houben, Tom
AU - Bitorina, Albert
AU - Oligschlaeger, Yvonne
AU - Jeurissen, Mike L. J.
AU - Rensen, Sander
AU - Kohler, S. Eleonore
AU - Westerterp, Marit
AU - Luetjohann, Dieter
AU - Theys, Jan
AU - Romano, Andrea
AU - Plat, Jogchum
AU - Shiri-Sverdlov, Ronit
N1 - Funding Information:
We wish to thank Patrick van Gorp, Dennis Meesters, and Marion Gijbels for excellent technical assistance. This research was supported by the Netherlands Organisation for Scientific Research (NWO) (Vidi grant No 016.126.327; ASPASIA grant No 015.008.043 to RSS, and Vidi grant No 91715350 to MW), by the CVON (CVON IN‐CONTROL 2012‐03), by the KWF Kankerbestrijding (Unique High Risk Project grant No 10820), and a Rosalind Franklin Fellowship from the University of Groningen to MW.
Publisher Copyright:
© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
PY - 2020/8
Y1 - 2020/8
N2 - Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in thesein vivomodels differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1(nih)) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17 beta-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and maleNpc1(nih)mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in femaleNpc1(nih)mice in contrast to maleNpc1(nih)mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ER alpha expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ER alpha expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. (c) 2020 The Authors.The Journal of Pathologypublished by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
AB - Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in thesein vivomodels differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1(nih)) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17 beta-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and maleNpc1(nih)mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in femaleNpc1(nih)mice in contrast to maleNpc1(nih)mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ER alpha expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ER alpha expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. (c) 2020 The Authors.The Journal of Pathologypublished by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
KW - 27-hydroxycholesterol
KW - inflammation
KW - sex differences
KW - estrogen
KW - CORONARY-HEART-DISEASE
KW - NONALCOHOLIC STEATOHEPATITIS
KW - CARDIOVASCULAR-DISEASE
KW - HEPATIC INFLAMMATION
KW - GENDER-DIFFERENCES
KW - CHOLESTEROL
KW - OBESITY
KW - RESPONSES
KW - MOUSE
KW - ACID
U2 - 10.1002/path.5477
DO - 10.1002/path.5477
M3 - Article
C2 - 32472585
SN - 0022-3417
VL - 251
SP - 429
EP - 439
JO - Journal of Pathology
JF - Journal of Pathology
IS - 4
ER -