Control of RSV-induced lung injury by alternatively activated macrophages is IL-4Rα-, TLR4-, and IFN-β-dependent (137.8)

• Published in: The Journal of immunology (1950) 2010-04, Vol.184 (1_Supplement), p.137-137.8
• Main Authors: Shirey, Kari Ann, Pletneva, Lioubov, Puche, Adam, Keegan, Achsah, Prince, Gregory, Blanco, Jorge, Vogel, Stefanie
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.184.Supp.137.8

Severe RSV-induced bronchiolitis has been associated with a mixed “Th1” and “Th2” cytokine storm. We hypothesized that differentiation of “alternatively activated” macrophages (AA-Mϕ) would mediate resolution of RSV-induced lung injury. RSV infection of murine lung and peritoneal macrophages resulted in IL-4 and IL-13 production, IL-4Rα/STAT6-dependent AA-Mϕ differentiation, and led to significantly enhanced inflammation in lungs of IL-4Rα-/- mice. Adoptive transfer of wild-type macrophages to IL-4Rα-/- mice restored RSV-inducible AA-Mϕ phenotype and diminished lung pathology. RSV-infected TLR4-/- and IFN-β-/- macrophages and mice also failed to express AA-Mϕ markers, but exhibited sustained proinflammatory cytokine production (e.g., IL-12) in vitro and in vivo and epithelial damage in vivo. TLR4 signaling was required for PPARγ expression, a DNA-binding protein that induces AA-Mϕ genes, while IFN-β regulates IL-4, IL-13, IL-4Rα, and IL-10 expression in response to RSV. RSV-infected cotton rats treated with a COX-2 inhibitor increased expression of lung AA-Mϕ. These data suggest novel treatment approaches for RSV that promote AA-Mϕ differentiation.