25-Hydroxycholesterol acts as an amplifier of inflammatory signaling
Elizabeth S. Gold,Alan H. Diercks,Irina Podolsky,Rebecca L. Podyminogin,Peter S. Askovich,Piper M. Treuting,Alan Aderem +6 more
Reads0
Chats0
TLDR
This study demonstrates, for the first time, 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.Abstract:
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.read more
Citations
More filters
Journal ArticleDOI
Cholesterol, inflammation and innate immunity
TL;DR: Therapeutic interventions such as increased production or infusion of high-density lipoproteins may sever the links between cholesterol accumulation and inflammation, and have beneficial effects in patients with metabolic diseases.
Journal ArticleDOI
Host Immune Response to Influenza A Virus Infection.
Xiaoyong Chen,Shasha Liu,Mohsan Ullah Goraya,Mohamed Maarouf,Shile Huang,Ji-Long Chen,Ji-Long Chen +6 more
TL;DR: How immune system, especially innate immune system and critical molecules are involved in the antiviral defense against IAVs is discussed and how IAV's antagonize different immune responses to achieve a successful infection is highlighted.
Journal ArticleDOI
25-Hydroxycholesterols in innate and adaptive immunity
TL;DR: The current understanding of the closely related oxysterols 25-hydroxycholesterol and 7α,25-dihydroxych cholesterol and the growing evidence that they have wide-ranging influences on innate and adaptive immunity are summarized.
Journal ArticleDOI
Oxysterols: From cholesterol metabolites to key mediators
TL;DR: The complex metabolism and molecular targets (including binding properties) of these bioactive lipids in human and mice are discussed and the genetic mouse models currently available to interrogate their effects in pathophysiological settings are discussed.
Journal ArticleDOI
Srebp-controlled glucose metabolism is essential for NK cell functional responses
Nadine Assmann,Katie L. O’Brien,Raymond P. Donnelly,Lydia Dyck,Vanessa Zaiatz-Bittencourt,Róisín M. Loftus,Paul Heinrich,Peter J. Oefner,Lydia Lynch,Clair M. Gardiner,Katja Dettmer,David K. Finlay +11 more
TL;DR: It is demonstrated that an essential role for Srebp transcription factors in cytokine-induced metabolic reprogramming of NK cells that was independent of their conventional role in the control of lipid synthesis is demonstrated.
References
More filters
Journal ArticleDOI
Exploration, normalization, and summaries of high density oligonucleotide array probe level data
Rafael A. Irizarry,Bridget G. Hobbs,Francois Collin,Yasmin Beazer-Barclay,Kristen J. Antonellis,Uwe Scherf,Terence P. Speed +6 more
TL;DR: There is no obvious downside to using RMA and attaching a standard error (SE) to this quantity using a linear model which removes probe-specific affinities, and the exploratory data analyses of the probe level data motivate a new summary measure that is a robust multi-array average (RMA) of background-adjusted, normalized, and log-transformed PM values.
Journal ArticleDOI
The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation
Mercedes Ricote,Andrew C. Li,Andrew C. Li,Timothy M. Willson,Carolyn J. Kelly,Christopher K. Glass +5 more
TL;DR: It is shown that PPAR-γ is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPar-γ ligands, suggesting that PPARS and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses.
Journal ArticleDOI
PPAR-γ agonists inhibit production of monocyte inflammatory cytokines
TL;DR: Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).
Journal ArticleDOI
AP-1 function and regulation.
TL;DR: This work has shown that regulation by heterodimerization between Jun, Fos and ATF proteins, AP-1 activity is regulated through interactions with specific protein kinases and a variety of transcriptional coactivators, and there has been considerable progress in understanding some of the mechanisms and signaling pathways involved in the regulation of AP.
Journal ArticleDOI
Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data.
Manhong Dai,Pinglang Wang,Andrew D. Boyd,Georgi Kostov,Brian D. Athey,Edward G. Jones,William E. Bunney,Richard M. Myers,Terry P. Speed,Huda Akil,Stanley J. Watson,Fan-Dong Meng +11 more
TL;DR: This work reorganized probes on more than a dozen popular GeneChips into gene-, transcript- and exon-specific probe sets in light of up-to-date genome, cDNA/EST clustering and single nucleotide polymorphism information, and demonstrates that the original Affymetrix probe set definitions are inaccurate.
Related Papers (5)
The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response
Mathieu Blanc,Wei Yuan Hsieh,Kevin A. Robertson,Kai A. Kropp,Thorsten Forster,Guanghou Shui,Paul Lacaze,Steven Watterson,Samantha J. Griffiths,Nathanael J. Spann,Anna Meljon,Simon G. Talbot,Kathiresan Krishnan,Douglas F. Covey,Markus R. Wenk,Marie Craigon,Zsolts Ruzsics,Jürgen Haas,Ana Angulo,William J. Griffiths,Christopher K. Glass,Yuqin Wang,Peter Ghazal +22 more