The TLR4 antagonist Eritoran protects mice from lethal influenza infection

Shirey, Kari Ann; Wei, Lai; Scott, Alison; Lipsky, Michael; Mistry, Pragnesh; Pletneva, Lioubov M.; Karp, Christopher L.; McAlees, Jaclyn W.; Gioannini, Theresa L.; Weiss, Jerrold; Chen, Wilbur H.; Ernst, Robert K.; Rossignol, Daniel P.; Gusovsky, Fabián; Blanco, Jorge C. G.; Vogel, Stefanie N.

doi:10.1038/nature12118

Cited by 384 publications

(451 citation statements)

References 31 publications

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“…Such therapeutic strategies could interfere with host signalling pathways necessary for viral replication, inhibit exaggerated inflammation, or promote tissue regeneration in an effort to dampen organ dysfunction and injury [196]. Strategies that limit immune responses, for example, by inhibiting the activation of TLR4 by oxidised phospholipids [80,197], targeting the S1P receptor or the angiotensin/ACE system [124,126,197,198] or even attenuating the production of type I IFNs [107], have been shown to reduce the severity of IAV-induced mortality in murine models. Similarly, strategies that promote immune resolution or tissue regeneration, e.g.…”

Section: Discussionmentioning

confidence: 99%

Influenza virus-induced lung injury: pathogenesis and implications for treatment

et al. 2015

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The influenza viruses are some of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. In humans, infection of the lower respiratory tract of can result in flooding of the alveolar compartment, development of acute respiratory distress syndrome and death from respiratory failure. Influenza-mediated damage of the airway, alveolar epithelium and alveolar endothelium results from a combination of: 1) intrinsic viral pathogenicity, attributable to its tropism for host airway and alveolar epithelial cells; and 2) a robust host innate immune response, which, while contributing to viral clearance, can worsen the severity of lung injury. In this review, we summarise the molecular events at the virus-host interface during influenza virus infection, highlighting some of the important cellular responses. We discuss immune-mediated viral clearance, the mechanisms promoting or perpetuating lung injury, lung regeneration after influenza-induced injury, and recent advances in influenza prevention and therapy. @ERSpublications We discuss novel aspects of virus-and immune-mediated lung injury and repair after influenza infection

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Section: Discussionmentioning

confidence: 99%

Influenza virus-induced lung injury: pathogenesis and implications for treatment

et al. 2015

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“…competitively inhibits binding of lipid A to MD2 and thereby inhibits downstream signaling (26). Eritoran was also shown to bind to CD14 and block the transfer of lipid A to MD2 (27). Eritoran blocks LPS-induced MyD88-and TRIF-dependent cytokine production in human and murine macrophages (28).…”

Section: Resultsmentioning

confidence: 99%

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

Rajesh

Perkins

Ireland

et al. 2015

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

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Dimerization of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) heterodimers is critical for both MyD88-and TIRdomain-containing adapter-inducing IFN-β (TRIF)-mediated signaling pathways. Recently, Zanoni et al. [(2011) Cell 147(4):868-880] reported that cluster of differentiation 14 (CD14) is required for LPS-/Escherichia coli-induced TLR4 internalization into endosomes and activation of TRIF-mediated signaling in macrophages. We confirmed their findings with LPS but report here that CD14 is not required for receptor endocytosis and downstream signaling mediated by TLR4/MD2 agonistic antibody (UT12) and synthetic small-molecule TLR4 ligands (1Z105) in murine macrophages. CD14 deficiency completely ablated the LPS-induced TBK1/IRF3 signaling axis that mediates production of IFN-β in murine macrophages without affecting MyD88-mediated signaling, including NF-κB, MAPK activation, and TNF-α and IL-6 production. However, neither the MyD88-nor TRIF-signaling pathways and their associated cytokine profiles were altered in the absence of CD14 in UT12-or 1Z105-treated murine macrophages. Eritoran (E5564), a lipid A antagonist that binds the MD2 "pocket," completely blocked LPS-and 1Z105-driven, but not UT12-induced, TLR4 dimerization and endocytosis. Furthermore, TLR4 endocytosis is induced in macrophages tolerized by exposure to either LPS or UT12 and is independent of CD14. These data indicate that TLR4 receptor endocytosis and the TRIF-signaling pathway are dissociable and that TLR4 internalization in macrophages can be induced by UT12, 1Z105, and during endotoxin tolerance in the absence of CD14. T oll-like receptor 4 (TLR4) signaling plays a crucial role in host defense against Gram-negative bacteria by recognizing the outer membrane component, lipopolysaccharide (LPS) (1-3). TLR4 signaling is initiated by transfer of an LPS monomer from LPS binding protein (LBP) to cluster of differentiation 14 (CD14) (GPI-linked or soluble). In turn, CD14 transfers monomeric LPS to myeloid differentiation factor 2 (MD-2), a protein that associates noncovalently with TLR4 (4). Appropriate ligand binding to MD2 results in dimerization of two TLR4/MD2 complexes (4). TLR4 is unique in that it is the only TLR that activates both myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adapter-inducing IFN-β (TRIF)-dependent signaling pathways (5, 6). MyD88-mediated, TLR4 signaling occurs mainly at plasma membranes and involves IL-1R-associated kinases phosphorylation, association of TNF-receptor-associated factor 6, and downstream signaling that results in NF-κB activation and induction of proinflammatory mediators such as TNF-α and IL-6 (7). In contrast, TRIF-mediated signaling in response to LPS occurs at the endosomal membrane after internalization of the TLR4 that, in turn, activates IFN regulatory factor 3 (IRF3), resulting in production of IFN-β, IP-10, and other IRF-3-dependent genes, as well as delayed NF-κB activation (8). Recent studies have shown that the endocytosis of TLR4 is tight...

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“…This suggests that at this time, general or specific interventions can be implemented to avert SIRS. Although targeted therapies such as specific TLR4 inhibitors did not alter outcomes in patients with severe sepsis, 26,27 this may be due to the fact that patients were already critically unwell and at advanced stages of SIRS when given a TLR4 antagonist. We hypothesise that treating patients with TLR4 inhibitors or agents that impair signalling through TLR5 or NF-kB may provide therapeutic benefit before the clinical manifestations of SIRS or sepsis become apparent.…”

Section: Patients Who Develop Sirs Have a Greater Proportion Of Cd14mentioning

confidence: 99%

Systemic Inflammatory Response Syndrome After Major Abdominal Surgery Predicted by Early Upregulation of TLR4 and TLR5

et al. 2016

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Mini AbstractPatients undergoing major surgery are at risk of life-threatening complications including systemic inflammatory response syndrome (SIRS) and sepsis. Early post-operative expression of TLR4 and TLR5 and their downstream signalling pathways in monocytes leads to over-expression of IL-6 and can predict SIRS in patients undergoing hepatopancreaticobiliary surgery. Running Title -Monocyte dysfunction in post-operative SIRS AbstractObjective To study innate immune pathways in hepatopancreaticobiliary (HPB) surgical patients to understand mechanisms leading to enhanced inflammatory responses and identifying biomarkers of adverse clinical consequences. Summary Background Data Patients undergoing major abdominal surgery are at risk of life-threatening systemic inflammatory response syndrome (SIRS) and sepsis. Early identification of at-risk patients would allow tailored post-operative care and improve survival. Methods Two separate cohorts of patients undergoing major HPB surgery were studied (combined n=69). Bloods were taken pre-operatively, on day 1 and day 2 post-operatively. Peripheral blood mononuclear cells and serum were separated and immune phenotype and function assessed ex vivo. Results Early innate immune dysfunction was evident in 12 patients who subsequently developed SIRS (post-operative day 6) compared to 27 who did not, when no clinical evidence of SIRS was apparent (pre-operatively or days 1 and 2). Serum interleukin (IL)-6 concentration and monocyte TLR/NF-DB/IL-6 functional pathways were significantly upregulated and overactive in patients who developed SIRS (p<0.0001). Interferon alpha-mediated STAT1 phosphorylation was higher pre-operatively in patients who developed SIRS. Increased TLR4 and TLR5 gene expression in whole blood was demonstrated in a separate validation cohort of 30 patients undergoing similar surgery. Expression of TLR4/5 on monocytes, particularly intermediate CD14 ++ CD16 + monocytes, on day 1 or 2 predicted SIRS with accuracy 0.89-1.0 (areas under receiver operator curves). Conclusions These data demonstrate the mechanism for IL-6 overproduction in patients who develop post-operative SIRS and identify markers that predict patients at risk of SIRS 5 days before onset of 30 patients undergoing similar surgery. Expression of TLR4/5 on monocytes, particularly intermediate CD14 ++ CD16 + monocytes, on day 1 or 2 predicted SIRS with accuracy 0.89-1.0 (areas under receiver operator curves).

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The TLR4 antagonist Eritoran protects mice from lethal influenza infection

Cited by 384 publications

References 31 publications

Influenza virus-induced lung injury: pathogenesis and implications for treatment

Influenza virus-induced lung injury: pathogenesis and implications for treatment

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

Systemic Inflammatory Response Syndrome After Major Abdominal Surgery Predicted by Early Upregulation of TLR4 and TLR5

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