Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology.
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.
Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA.
K A
KA
Shirey
Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA.
W
W
Lai
Sigmovir Biosystems, Inc., Rockville, Maryland, USA.
L M
LM
Pletneva
Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
C L
CL
Karp
Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
S
S
Divanovic
Sigmovir Biosystems, Inc., Rockville, Maryland, USA.
J C G
JC
Blanco
Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA.
S N
SN
Vogel
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D012136:Respiratory Syncytial Viruses; D015398:Signal Transduction
D016861:Cyclooxygenase Inhibitors; D012333:RNA, Messenger; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases