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Agents that increase AAM differentiation blunt RSV-mediated lung pathology
Kari Ann Shirey1, Wendy Lai1, Lioubov M Pletneva2
1Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA;
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.
Insights
Respiratory Syncytial Virus (RSV) infection causes severe lung disease in infants. Enhancing alternatively activated macrophages (AAMs) through therapeutic interventions can reduce RSV-induced lung pathology and offers a promising treatment strategy.
Area of Science:
- Immunology
- Respiratory Medicine
- Infectious Diseases
Background:
- Respiratory Syncytial Virus (RSV) is a major cause of severe lower respiratory tract infections in infants globally.
- Current treatments for RSV lack efficacy, and no vaccine is available.
- Alternatively activated macrophages (AAMs) have been identified as key mediators in resolving RSV-induced lung pathology.
Purpose of the Study:
- To investigate the potential of therapeutically enhancing AAM differentiation to mitigate RSV-induced lung disease.
- To explore specific molecular pathways and agents that promote AAM development in the context of RSV infection.
Main Methods:
- Utilized mouse models of RSV infection.
- Administered IL-4/anti-IL-4 immune complexes to sustain IL-4 levels.
- Induced AAM development using rosiglitazone (a PPARγ agonist) and azithromycin (AZM).
- Assessed AAM markers (arginase-1, mannose receptor) and lung pathology.
Main Results:
- Treatment with IL-4/anti-IL-4 immune complexes increased AAM markers and reduced lung pathology in RSV-infected mice.
- Induction of PPARγ with rosiglitazone or treatment with AZM also enhanced AAM markers and mitigated lung inflammation.
- These findings demonstrate that promoting AAMs can counteract RSV-induced lung damage.
Conclusions:
- Therapeutic strategies aimed at enhancing AAM differentiation represent a viable approach for treating RSV-induced lung disease.
- Modulating macrophage phenotypes offers a novel therapeutic avenue for managing severe respiratory infections.
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