title: Agents that increase AAM differentiation blunt RSV-mediated lung pathology.
abstract: RSV is the most significant cause of serious lower respiratory tract infection in infants and young children worldwide. There is currently no vaccine for the virus, and antiviral therapy (e.g., ribavirin) has shown no efficacy against the disease. We reported that alternatively activated macrophages (AAMs) mediate resolution of RSV-induced pathology. AAM differentiation requires macrophage-derived IL-4 and -13, autocrine/paracrine signaling through the type I IL-4 receptor, and STAT6 activation. Based on these findings, we reasoned that it would be possible to intervene therapeutically in RSV disease by increasing AAM differentiation, thereby decreasing lung pathology. Mice treated with the IL-4/anti-IL-4 immune complexes, shown previously to sustain levels of circulating IL-4, increased the RSV-induced AAM markers arginase-1 and mannose receptor and decreased the lung pathology. Induction of PPARγ, shown to play a role in AAM development, by the PPARγ agonist rosiglitazone or treatment of mice with the macrolide antibiotic AZM, also reported to skew macrophage differentiation to an AAM phenotype, increased the AAM markers and mitigated RSV-induced lung pathology. Collectively, our data suggest that therapeutic manipulation of macrophage differentiation to enhance the AAM phenotype is a viable approach for ameliorating RSV-induced disease.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA;
authors.forename: Kari Ann
authors.initials: KA
authors.lastname: Shirey
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA;
authors.forename: Wendy
authors.initials: W
authors.lastname: Lai
authors.affiliation: Sigmovir Biosystems, Inc., Rockville, Maryland, USA;
authors.forename: Lioubov M
authors.initials: LM
authors.lastname: Pletneva
authors.affiliation: Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA; Division of Allergy, Immunology and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; and.
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.affiliation: University of Kentucky, College of Pharmacy, Lexington, Kentucky, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Feola
authors.affiliation: Sigmovir Biosystems, Inc., Rockville, Maryland, USA;
authors.forename: Jorge C G
authors.initials: JC
authors.lastname: Blanco
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA; svogel@som.umaryland.edu.
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000627:therapeutic use*; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D001119:Arginase / Q000096:biosynthesis / Q000235:genetics; D017963:Azithromycin / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000473:pathology* / Q000821:virology; D008264:Macrophages / Q000187:drug effects*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000627:therapeutic use; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000473:pathology; D000077154:Rosiglitazone; D050800:STAT6 Transcription Factor / Q000502:physiology; D016205:Sigmodontinae; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000936:Antigen-Antibody Complex; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D047495:PPAR gamma; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015847:Interleukin-4; D017963:Azithromycin; D001094:Arachidonate 5-Lipoxygenase; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: PPARγ; azithromycin; macrophage differentiation; rosiglitazone