Control of RSV-induced lung injury by alternatively activated macrophages is IL-4R alpha-, TLR4-, and IFN-beta-dependent.
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.
Shirey
K A
KA
Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), Baltimore, MD, USA.
Pletneva
L M
LM
Puche
A C
AC
Keegan
A D
AD
Prince
G A
GA
Blanco
J C G
JC
Vogel
S N
SN
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055370:Lung Injury / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology* / Q000378:metabolism; D016205:Sigmodontinae; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit
D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D016899:Interferon-beta; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C493487:Tlr4 protein, mouse
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