25-Hydroxycholesterols in innate and adaptive immunity

Cyster, Jason G.; Dang, Eric V.; Reboldi, Andrea; Yi, Tangsheng

doi:10.1038/nri3755

Cited by 307 publications

(326 citation statements)

References 129 publications

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“…It is well known that 25HC inhibits SREBP-2 activation and thereby also reduces Srebf-2 expression through Srebf-2 autoregulation (21). Given this, we speculated that an IFN␤-Ch25h-25HC axis downstream of TRIF might mediate Srebf-2 down-regulation at late time points after LPS.…”

Section: Mir-33 Expression Is Down-regulated By Multiple Tlrmentioning

confidence: 98%

MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains

Lai

Azzam

Lin

et al. 2016

Journal of Biological Chemistry

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MicroRNAs (miRNAs) 3 are small (ϳ22-nucleotide) noncoding RNAs that regulate gene expression by binding to partially complementary sites in the 3Ј-untranslated regions (UTRs) of specific mRNAs, thereby promoting degradation and/or repressing translation of target mRNAs. The human genome contains Ͼ2500 unique mature miRNAs (1). Because individual miRNAs typically have multiple targets, it is thought that Ͼ60% of all human genes may be subject to regulation by miRNAs (2). The promiscuity of miRNAs for target RNAs is expected to represent a fundamental mechanism of cross-talk and coordination among signaling networks in development, health, and disease.Among the signaling networks that have been shown in recent years to be regulated by miRNAs are the Toll-like receptors (TLRs) of the innate immune system. Multiple TLRs up-regulate miRNAs, including miR-155, miR-146, miR-21, miR-147, and miR-9, whereas activation of TLR4 by lipopolysaccharide (LPS) down-regulates a distinct set of miRNAs (3, 4). In turn, miRNAs "fine tune" the proinflammatory signaling output of TLR cascades by controlling the expression of TLR pathway members (3, 4). Thus, miR-146 suppresses signaling by multiple TLRs via targeting the common signaling hubs IL-1 receptor-associated kinase 1 and TNF receptor-associated factor 6 (5), whereas miR-155 has complex effects, repressing the TLR adaptor myeloid differentiation primary response 88 (MyD88) (6, 7) and TAK1-binding protein 2 (8), an upstream activator of the mitogen-activated protein kinases, but also promoting cytokine expression through actions on other targets (3). Although virtually all known examples of TLR regulation by miRNAs operate through direct targeting of TLR pathway components, it is expected that miRNAs may also indirectly impact the innate immune response by regulating other networks that cross-talk with TLRs.miR-33a and miR-33b (present in primates but absent in rodents and lower species in which miR-33a is simply referred to as "miR-33") are now known to be master regulators of cho-

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Section: Mir-33 Expression Is Down-regulated By Multiple Tlrmentioning

confidence: 98%

MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains

Lai

Azzam

Lin

et al. 2016

Journal of Biological Chemistry

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“…The different outcomes observed following the treatment of tumors with molecules stimulating or interfering with LXR/LXR ligands should take into account the tumor models used, the presence of an intact immune system, the distinct isoforms of LXRs engaged, and the intrinsic biologic ability of oxysterols to bind receptors different from LXRs (12,35). Therefore, appropriate models dissecting how LXR/LXR ligands operate within the tumor microenvironment are required.…”

Section: Discussionmentioning

confidence: 99%

24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

Soncini

Corna

Moresco

et al. 2016

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

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Cells in the tumor microenvironment may be reprogrammed by tumor-derived metabolites. Cholesterol-oxidized products, namely oxysterols, have been shown to favor tumor growth directly by promoting tumor cell growth and indirectly by dampening antitumor immune responses. However, the cellular and molecular mechanisms governing oxysterol generation within tumor microenvironments remain elusive. We recently showed that tumorderived oxysterols recruit neutrophils endowed with protumoral activities, such as neoangiogenesis. Here, we show that hypoxia inducible factor-1a (HIF-1α) controls the overexpression of the enzyme Cyp46a1, which generates the oxysterol 24-hydroxycholesterol (24S-HC) in a pancreatic neuroendocrine tumor (pNET) model commonly used to study neoangiogenesis. The activation of the HIF-1α-24S-HC axis ultimately leads to the induction of the angiogenic switch through the positioning of proangiogenic neutrophils in proximity to Cyp46a1 + islets. Pharmacologic blockade or genetic inactivation of oxysterols controls pNET tumorigenesis by dampening the 24S-HC-neutrophil axis. Finally, we show that in some human pNET samples Cyp46a1 transcripts are overexpressed, which correlate with the HIF-1α target VEGF and with tumor diameter. This study reveals a layer in the angiogenic switch of pNETs and identifies a therapeutic target for pNET patients.oxysterols | HIF-1α | pancreatic neuroendocrine tumors | angiogenic switch | neutrophils R ecent studies have highlighted the diversity of metabolic pathways altered between normal and tumor cells (1, 2). Activation of specific metabolic pathways within tumors is believed to derive from an intricate connection among intrinsic and extrinsic factors, such as oncogenic signaling, stromal-derived molecules, and hypoxia (3). Tumor hypoxia and hypoxia inducible factor-1a (HIF-1α) activation have been linked to increased glucose metabolism and cancer progression in a number of tumor types (4). Whether HIF-1α signaling regulates other metabolic products in tumor cells or during tumorigenesis remains only partially understood.The differential regulation of tumor metabolism and the relative abundance of some tumor-derived metabolites have also been shown to condition the tumor microenvironment, with particular emphasis on immune cell components (5). For example, metabolic products like pyruvic acid and lactic acid induce hypoxiaindependent stabilization of HIF-1α in tumor-associated macrophages (6). These products, especially lactic acid, are products of the so-called Warburg effect (aerobic glycolysis) (7) and mainly require the enzymatic activity of the pyruvate kinase M2 (PKM2), an isoform expressed by tumor cells and associated with the production of high amounts of pyruvate and lactate (8). More recently cholesterol metabolism, oxysterols, and liver X receptors (LXRs) have been shown to be important players in tumor metabolism (9, 10), due to their dual involvement in tumor and immune cell biology (11-13). This dual involvement makes the LXR/oxysterol axis an attractive ta...

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“…In addition to its potent inhibitory effects on the SREBPs maturation, recent studies have expanded its roles in immune systems. 25HC has a wide range of immunological effects, including suppressing the production of IgA by B cells, regulating immune cell migration, differentiation, and modulating inflammatory signaling (16). Ch25h is upregulated in murine macrophages in response to Toll-like receptor (TLR) ligand stimulation, suggesting that Ch25h represents a host response against virus infection (17)(18)(19).…”

mentioning

confidence: 99%

Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

Tang

Tao

et al. 2015

J Virol

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Hepatitis C virus (HCV), a single-stranded positive-sense RNA virus of the Flaviviridae family, causes chronic liver diseases, including hepatitis, cirrhosis, and cancer. HCV infection is critically dependent on host lipid metabolism, which contributes to all stages of the viral life cycle, including virus entry, replication, assembly, and release. 25-Hydroxycholesterol (25HC) plays a critical role in regulating lipid metabolism, modulating immune responses, and suppressing viral pathogens. In this study, we showed that 25HC and its synthesizing enzyme cholesterol 25-hydroxylase (CH25H) efficiently inhibit HCV infection at a postentry stage. CH25H inhibits HCV infection by suppressing the maturation of SREBPs, critical transcription factors for host lipid biosynthesis. Interestingly, CH25H is upregulated upon poly(I·C) treatment or HCV infection in hepatocytes, which triggers type I and III interferon responses, suggesting that the CH25H induction constitutes a part of host innate immune response. To our surprise, in contrast to studies in mice, CH25H is not induced by interferons in human cells and knockdown of STAT-1 has no effect on the induction of CH25H, suggesting CH25H is not an interferon-stimulated gene in humans but rather represents a primary and direct host response to viral infection. Finally, knockdown of CH25H in human hepatocytes significantly increases HCV infection. In summary, our results demonstrate that CH25H constitutes a primary innate response against HCV infection through regulating host lipid metabolism. Manipulation of CH25H expression and function should provide a new strategy for anti-HCV therapeutics. IMPORTANCERecent studies have expanded the critical roles of oxysterols in regulating immune response and antagonizing viral pathogens. Here, we showed that one of the oxysterols, 25HC and its synthesizing enzyme CH25H efficiently inhibit HCV infection at a postentry stage via suppressing the maturation of transcription factor SREBPs that regulate lipid biosynthesis. Furthermore, we found that CH25H expression is upregulated upon poly(I·C) stimulation or HCV infection, suggesting CH25H induction constitutes a part of host innate immune response. Interestingly, in contrast to studies in mice showing that ch25h is an interferon-stimulated gene, CH25H cannot be induced by interferons in human cells but rather represents a primary and direct host response to viral infection. Our studies demonstrate that the induction of CH25H represents an important host innate response against virus infection and highlight the role of lipid effectors in host antiviral strategy. H epatitis C virus (HCV), a causative agent of acute and chronic liver diseases, is an enveloped positive-sense single-stranded RNA virus belonging to the family of Flaviviridae. Approximately 170 million people worldwide are infected with HCV. The tremendous progress has been achieved in the therapeutics of chronic hepatitis C thanks to the development of direct antiviral agents (DAAs), but the worldwide application of the...

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25-Hydroxycholesterols in innate and adaptive immunity

Cited by 307 publications

References 129 publications

MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains

MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains

24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

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