25-Hydroxycholesterol Activates the Integrated Stress Response to Reprogram Transcription and Translation in Macrophages

Shibata, Norihito; Carlin, Aaron F.; Spann, Nathanael J.; Saijo, Kaoru; Morello, Christopher S.; McDonald, Jeffrey G.; Romanoski, Casey E.; Maurya, Mano Ram; Kaikkonen, Minna U.; Lam, Michael T.; Crotti, Andrea; Reichart, Donna; Fox, Jesse N.; Quehenberger, Oswald; Raetz, Christian R. H.; Sullards, M. Cameron; Murphy, Robert C.; Merrill, Alfred H.; Brown, H. Alex; Dennis, Edward A.; Fahy, Eoin; Subramaniam, Shankar; Cavener, Douglas R.; Spector, Deborah H.; Russell, David W.; Glass, Christopher K.

doi:10.1074/jbc.m113.519637

Cited by 67 publications

(68 citation statements)

References 67 publications

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“…Recent work by Shibata et al has demonstrated that 25HC can alter the transcriptional and translational program in macrophages by affecting the endoplasmic reticulum (ER) stress response (29). Our transcriptomic data are concordant with this study as we also detected increases in several stress response genes following stimulation of macrophages with 25HC, including Chac1, Trib3, Ddit3, Atf4, and Asns (GSE54064).…”

Section: Discussionsupporting

confidence: 81%

25-Hydroxycholesterol acts as an amplifier of inflammatory signaling

Gold

Diercks

Podolsky

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

222

198

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Cross-talk between sterol regulatory pathways and inflammatory pathways has been demonstrated to significantly impact the development of both atherosclerosis and infectious disease. The oxysterol 25-hydroxycholesterol (25HC) plays multiple roles in lipid biosynthesis and immunity. We recently used a systems biology approach to identify 25HC as an innate immune mediator that had a predicted role in atherosclerosis and we demonstrated a role for 25HC in foam cell formation. Here, we show that this mediator also has several complex roles in the antiviral response. The host response to viruses involves gene regulatory circuits with multiple feedback loops and we show here that 25HC acts as an amplifier of inflammatory signaling in macrophages. We determined that 25HC amplifies inflammatory signaling, at least in part, by mediating the recruitment of the AP-1 components FBJ osteosarcoma oncogene (FOS) and jun proto-oncogene (JUN) to the promoters of a subset of Toll-like receptor-responsive genes. Consistent with previous reports, we found that 25HC inhibits in vitro infection of airway epithelial cells by influenza. Surprisingly, we found that deletion of Ch25h, the gene encoding the enzyme responsible for 25HC production, is protective in a mouse model of influenza infection as a result of decreased inflammatory-induced pathology. Thus, our study demonstrates, for the first time to our knowledge, that in addition to its direct antiviral role, 25HC also regulates transcriptional responses and acts as an amplifier of inflammation via AP-1 and that the resulting alteration in inflammatory response leads to increased tissue damage in mice following infection with influenza.

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Section: Discussionsupporting

confidence: 81%

25-Hydroxycholesterol acts as an amplifier of inflammatory signaling

Gold

Diercks

Podolsky

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

222

198

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“…Our results showed that 25HC could inhibit ZIKV infection in type I IFN signaling deficient A549 cells and in Ifnar −/− mice. However, 25HC may suppress ZIKV infection through other immune pathways, like activating integrated stress response (ISR) genes (Shibata et al, 2013) or the TLR4-dependent NF-kB pathway as described (Aye et al, 2012), which needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model

et al. 2017

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SUMMARY Zika virus (ZIKV) has become a public health threat due to its global transmission and link to severe congenital disorders. The host immune responses to ZIKV infection have not been fully elucidated, and effective therapeutics are not currently available. Herein, we demonstrated that cholesterol-25-hydroxylase (CH25H) was induced in response to ZIKV infection and that its enzymatic product, 25-hydroxycholesterol (25HC), was a critical mediator of host protection against ZIKV. Synthetic 25HC addition inhibited ZIKV infection in vitro by blocking viral entry, and treatment with 25HC reduced viremia and conferred protection against ZIKV in mice and rhesus macaques. 25HC suppressed ZIKV infection and reduced tissue damage in human cortical organoids and the embryonic brain of the ZIKV-induced mouse microcephaly model. Our findings highlight the protective role of CH25H during ZIKV infection and the potential use of 25HC as a natural antiviral agent to combat ZIKV infection and prevent ZIKV-associated outcomes, such as microcephaly.

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“…Therefore, we presume that activation of both the IRE1 and PERK arms is necessary for the induction of apoptosis. In this context, Shibata et al ( 53 ) have recently reported that 25-HC triggers integrated stress response via activation of GCN2/eIF2/ATF4 in macrophages. It would be intriguing to know whether the same pathway is activated in the Nceh1-dependent augmentation of 25-HC-induced ER stress, although it is beyond the scope of this study.…”

Section: Lipe Is Not Involved In 25-hc-induced Augmentation Of Macropmentioning

confidence: 99%

Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages

Sekiya

Yamamuro

Ohshiro

et al. 2014

Journal of Lipid Research

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Atherosclerotic cardiovascular diseases are the leading cause of mortality in industrialized countries, despite advances in the management of coronary risk factors. Heart attacks arise from the thrombotic occlusion of coronary arteries following the rupture of plaques. Characteristic of these rupture-prone plaques is their lipid-rich nature due to the presence of cholesteryl ester (CE)-laden macrophage foam cells ( 1 ).The hydrolysis of intracellular CE, the initial step of reverse cholesterol transport, is catalyzed by multiple enzymes: neutral cholesterol ester hydrolase 1 (NCEH1) ( 2 ), also known as KIAA1363 or arylacetamide deacetylase-like 1 (AADACL1) ( 3 ), hormone-sensitive lipase (LIPE) ( 4 ), and possibly carboxylesterase 1 (CES1) ( 5, 6 ). NCEH1 is a microsomal protein tethered to the endoplasmic reticulum (ER) membrane by its N terminus with the rest of the protein containing the catalytic domain residing in the ER Abbreviations: acLDL, acetyl-LDL; Bip, immunoglobulin heavy chain-binding protein; CE, cholesteryl ester; CHOP, CCAAT/enhancer-binding protein-homologous protein; ER, endoplasmic reticulum; 25-HC, 25-hydroxycholesterol; 27-HC, 27-hydroxycholesterol; Hmgcs1 , 3-hydroxy-3-methylglutaryl-CoA synthase 1; 7-KC, 7-ketocholesterol; LD, lipid droplet; LIPE, hormone-sensitive lipase; LPDS, lipoprotein defi cient serum; LXR, liver X receptor; NCEH1, neutral cholesterol ester hydrolase 1; PPPA, pyripyropene A; Srebp, sterol regulatory element binding protein; TEM, transmission electron microscopy; TGEM, thioglycollate-elicited peritoneal macrophage; TUNEL, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; Xbp-1, X-box-binding protein 1 . This work was supported by a grant-in-aid from Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists, a grant-in-aid for Scientifi c Research from the Ministry of Education and Science, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) and JKA through its promotion funds from KEIRIN RACE, and MEXT-Supported Program for the Strategic Research

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25-Hydroxycholesterol Activates the Integrated Stress Response to Reprogram Transcription and Translation in Macrophages

Cited by 67 publications

References 67 publications

25-Hydroxycholesterol acts as an amplifier of inflammatory signaling

25-Hydroxycholesterol acts as an amplifier of inflammatory signaling

25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model

Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages

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