Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis

被引：132

作者：

Kim, Don-Kyu ^{[1
,2
]}

Jeong, Jae-Ho ^{[3
,4
]}

Lee, Ji-Min ^{[1
,2
]}

Kim, Kwang Soo ^{[3
,4
]}

Park, Seung-Hwan ^{[5
]}

Kim, Yong Deuk ^{[1
,2
]}

Koh, Minseob ^{[6
]}

Shin, Minsang ^{[1
,2
]}

Jung, Yoon Seok ^{[1
,2
]}

Kim, Hyung-Seok ^{[7
]}

Lee, Tae-Hoon ^{[4
,8
]}

Oh, Byung-Chul ^{[9
]}

Kim, Jae Il ^{[10
,11
]}

Park, Hwan Tae ^{[12
]}

Jeong, Won-Il ^{[13
]}

Lee, Chul-Ho ^{[14
]}

Park, Seung Bum ^{[6
,15
]}

Min, Jung-Joon ^{[4
,5
]}

Jung, Sook-In ^{[4
,16
]}

Choi, Seok-Yong ^{[17
]}

Choy, Hyon E. ^{[3
,4
]}

Choi, Hueng-Sik ^{[1
,2
]}

机构：

[1] Chonnam Natl Univ, Sch Biol Sci & Technol, Natl Creat Res Initiat, Ctr Nucl Receptor Signals, Kwangju, South Korea

[2] Chonnam Natl Univ, Sch Biol Sci & Technol, Hormone Res Ctr, Kwangju, South Korea

[3] Chonnam Natl Univ, Sch Med, Dept Microbiol, Kwangju, South Korea

[4] Chonnam Natl Univ, Grad Sch, Dept Mol Med BK21plus, Kwangju, South Korea

[5] Chonnam Natl Univ, Sch Med, Dept Nucl Med, Kwangju, South Korea

[6] Seoul Natl Univ, Coll Nat Sci, Dept Chem, Seoul 151742, South Korea

[7] Chonnam Natl Univ, Sch Med, Dept Forens Med, Kwangju, South Korea

[8] Chonnam Natl Univ, Dent Sci Res Inst, Dept Oral Biochem, Kwangju, South Korea

[9] Gachon Univ, Grad Sch Med, Lee Gil Ya Canc & Diabet Inst, Inchon, South Korea

[10] Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju, South Korea

[11] AnyGen, Jeonnam NanoBioRes Ctr, Jangseong Gun, South Korea

[12] Dong A Univ, Coll Med, Mitochondria Hub Regulat Ctr, Dept Physiol, Pusan, South Korea

[13] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Taejon 305701, South Korea

[14] Korea Res Inst Biosci & Biotechnol, Taejon, South Korea

[15] Seoul Natl Univ, Coll Nat Sci, Dept Biophys & Chem Biol, Seoul 151742, South Korea

[16] Chonnam Natl Univ, Sch Med, Dept Infect Dis, Kwangju, South Korea

[17] Chonnam Natl Univ, Sch Med, Dept Biomed Sci, Kwangju, South Korea

来源：

NATURE MEDICINE | 2014年 / 20卷 / 04期

基金：

新加坡国家研究基金会;

关键词：

ERR-GAMMA; HEPATIC GLUCONEOGENESIS; KEY REGULATOR; LIVER-INJURY; MACROPHAGES; HEPCIDIN; GROWTH; FERROPORTIN; METABOLISM; EXPRESSION;

D O I：

10.1038/nm.3483

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In response to microbial infection, expression of the defensin-like peptide hepcidin (encoded by Hamp) is induced in hepatocytes to decrease iron release from macrophages(1). To elucidate the mechanism by which Salmonella enterica var. Typhimurium (S. typhimurium), an intramacrophage bacterium, alters host iron metabolism for its own survival, we examined the role of nuclear receptor family members belonging to the NR3B subfamily in mouse hepatocytes. Here, we report that estrogen-related receptor gamma (ERR gamma, encoded by Esrrg) modulates the intramacrophage proliferation of S. typhimurium by altering host iron homeostasis, and we demonstrate an antimicrobial effect of an ERR gamma inverse agonist. Hepatic ERR gamma expression was induced by S. typhimurium-stimulated interleukin-6 signaling, resulting in an induction of hepcidin and eventual hypoferremia in mice. Conversely, ablation of ERR gamma mRNA expression in liver attenuated the S. typhimurium-mediated induction of hepcidin and normalized the hypoferremia caused by S. typhimurium infection. An inverse agonist of ERR gamma ameliorated S. typhimurium-mediated hypoferremia through reduction of ERR gamma-mediated hepcidin mRNA expression and exerted a potent antimicrobial effect on the S. typhimurium infection, thereby improving host survival. Taken together, these findings suggest an alternative approach to control multidrug-resistant intracellular bacteria by modulating host iron homeostasis.

引用

页码：419 / +

页数：8

共 25 条

[1] ERRγ directs and maintains the transition to oxidative metabolism in the postnatal heart [J].