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1.
Mucosal Immunol ; 9(5): 1173-82, 2016 09.
Article in English | MEDLINE | ID: mdl-26813341

ABSTRACT

We previously reported that TLR4(-/-) mice are refractory to mouse-adapted A/PR/8/34 (PR8) influenza-induced lethality and that therapeutic administration of the TLR4 antagonist Eritoran blocked PR8-induced lethality and acute lung injury (ALI) when given starting 2 days post infection. Herein we extend these findings: anti-TLR4- or -TLR2-specific IgG therapy also conferred significant protection of wild-type (WT) mice from lethal PR8 infection. If treatment is initiated 3 h before PR8 infection and continued daily for 4 days, Eritoran failed to protect WT and TLR4(-/-) mice, implying that Eritoran must block a virus-induced, non-TLR4 signal that is required for protection. Mechanistically, we determined that (i) Eritoran blocks high-mobility group B1 (HMGB1)-mediated, TLR4-dependent signaling in vitro and circulating HMGB1 in vivo, and an HMGB1 inhibitor protects against PR8; (ii) Eritoran inhibits pulmonary lung edema associated with ALI; (iii) interleukin (IL)-1ß contributes significantly to PR8-induced lethality, as evidenced by partial protection by IL-1 receptor antagonist (IL-1Ra) therapy. Synergistic protection against PR8-induced lethality was achieved when Eritoran and the antiviral drug oseltamivir were administered starting 4 days post infection. Eritoran treatment does not prevent development of an adaptive immune response to subsequent PR8 challenge. Overall, our data support the potential of a host-targeted therapeutic approach to influenza infection.


Subject(s)
Acute Lung Injury/drug therapy , Antiviral Agents/pharmacology , Disaccharides/pharmacology , Immunoglobulin G/pharmacology , Orthomyxoviridae Infections/drug therapy , Oseltamivir/pharmacology , Sugar Phosphates/pharmacology , Acute Lung Injury/immunology , Acute Lung Injury/mortality , Acute Lung Injury/virology , Animals , Drug Synergism , Female , Gene Expression Regulation , HMGB1 Protein/antagonists & inhibitors , HMGB1 Protein/genetics , HMGB1 Protein/immunology , Immunity, Innate , Interleukin-1 Receptor Accessory Protein/antagonists & inhibitors , Interleukin-1 Receptor Accessory Protein/genetics , Interleukin-1 Receptor Accessory Protein/immunology , Lung/drug effects , Lung/immunology , Lung/pathology , Lung/virology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Targeted Therapy , Orthomyxoviridae/drug effects , Orthomyxoviridae/growth & development , Orthomyxoviridae/pathogenicity , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/mortality , Orthomyxoviridae Infections/virology , Signal Transduction , Survival Analysis , Toll-Like Receptor 2/antagonists & inhibitors , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/immunology , Toll-Like Receptor 4/antagonists & inhibitors , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunology
2.
Mucosal Immunol ; 7(3): 549-57, 2014 May.
Article in English | MEDLINE | ID: mdl-24064666

ABSTRACT

Resolution of severe Respiratory Syncytial Virus (RSV)-induced bronchiolitis is mediated by alternatively activated macrophages (AA-Mφ) that counteract cyclooxygenase (COX)-2-induced lung pathology. Herein, we report that RSV infection of 5-lipoxygenase (LO)(-/-) and 15-LO(-/-) macrophages or mice failed to elicit AA-Mφ differentiation and concomitantly exhibited increased COX-2 expression. Further, RSV infection of 5-LO(-/-) mice resulted in enhanced lung pathology. Pharmacologic inhibition of 5-LO or 15-LO also blocked differentiation of RSV-induced AA-Mφ in vitro and, conversely, treatment of 5-LO(-/-) macrophages with downstream products, lipoxin A4 and resolvin E1, but not leukotriene B4 or leukotriene D4, partially restored expression of AA-Mφ markers. Indomethacin blockade of COX activity in RSV-infected macrophages increased 5-LO and 15-LO, as well as arginase-1 mRNA expression. Treatment of RSV-infected mice with indomethacin also resulted not only in enhanced lung arginase-1 mRNA expression and decreased COX-2, but also decreased lung pathology in RSV-infected 5-LO(-/-) mice. Treatment of RSV-infected cotton rats with a COX-2-specific inhibitor resulted in enhanced lung 5-LO mRNA and AA-Mφ marker expression. Together, these data suggest a novel therapeutic approach for RSV that promotes AA-Mφ differentiation by activating the 5-LO pathway.


Subject(s)
Arachidonate 5-Lipoxygenase/metabolism , Macrophages/immunology , Macrophages/metabolism , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Viruses , Signal Transduction , Animals , Arachidonate 15-Lipoxygenase/genetics , Arachidonate 15-Lipoxygenase/metabolism , Arachidonate 5-Lipoxygenase/genetics , Cyclooxygenase Inhibitors/pharmacology , Disease Models, Animal , Enzyme Activation , Gene Expression Regulation , Macrophage Activation/immunology , Macrophages/drug effects , Macrophages/virology , Mice , Mice, Knockout , Prostaglandin-Endoperoxide Synthases/metabolism , RNA, Messenger/genetics , Rats , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus Infections/virology
3.
Mucosal Immunol ; 3(3): 291-300, 2010 May.
Article in English | MEDLINE | ID: mdl-20404812

ABSTRACT

Severe respiratory syncytial virus (RSV)-induced bronchiolitis has been associated with a mixed "Th1" and "Th2" cytokine storm. We hypothesized that differentiation of "alternatively activated" macrophages (AA-M phi) would mediate the resolution of RSV-induced lung injury. RSV induced interleukin (IL)-4 and IL-13 by murine lung and peritoneal macrophages, IL-4R alpha/STAT6-dependent AA-M phi differentiation, and significantly enhanced inflammation in the lungs of IL-4R alpha(-/-) mice. Adoptive transfer of wildtype macrophages to IL-4R alpha(-/-) mice restored RSV-inducible AA-M phi phenotype and diminished lung pathology. RSV-infected Toll-like receptor (TLR)4(-/-) and interferon (IFN)-beta(-/-) macrophages and mice also failed to express AA-M phi markers, but exhibited sustained proinflammatory cytokine production (e.g., IL-12) in vitro and in vivo and epithelial damage in vivo. TLR4 signaling is required for peroxisome proliferator-activated receptor gamma expression, a DNA-binding protein that induces AA-M phi genes, whereas IFN-beta regulates IL-4, IL-13, IL-4R alpha, and IL-10 expression in response to RSV. RSV-infected cotton rats treated with a cyclooxygenase-2 inhibitor increased expression of lung AA-M phi. These data suggest new treatment strategies for RSV that promote AA-M phi differentiation.


Subject(s)
Interferon-beta/immunology , Lung Injury/immunology , Macrophage Activation/immunology , Macrophages, Alveolar/immunology , Macrophages, Peritoneal/immunology , Receptors, Cell Surface/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/immunology , Toll-Like Receptor 4/immunology , Animals , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Differentiation/immunology , Cyclooxygenase 2 Inhibitors/pharmacology , Cytokines/genetics , Cytokines/immunology , Cytokines/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Humans , Interferon-beta/genetics , Interferon-beta/metabolism , Lung Injury/metabolism , Lung Injury/virology , Macrophage Activation/drug effects , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/virology , Macrophages, Peritoneal/metabolism , Macrophages, Peritoneal/virology , Mice , Mice, Inbred BALB C , Mice, Knockout , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia/virology , Rats , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/metabolism , Sigmodontinae , Signal Transduction/drug effects , Signal Transduction/immunology , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism
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