CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality.
Infection with pathogenic influenza virus induces severe pulmonary immune pathology, but the specific cell types that cause this have not been determined. We characterized inflammatory cell types in mice that overexpress MCP-1 (CCL2) in the lungs, then examined those cells during influenza infection of wild-type (WT) mice. Lungs of both naive surfactant protein C-MCP mice and influenza-infected WT mice contain increased numbers of CCR2(+) monocytes, monocyte-derived DC (moDC), and exudate macrophages (exMACs). Adoptively transferred Gr-1(+) monocytes give rise to both moDC and exMACs in influenza-infected lungs. MoDC, the most common inflammatory cell type in infected lungs, induce robust naive T cell proliferation and produce NO synthase 2 (NOS2), whereas exMACs produce high levels of TNF-alpha and NOS2 and stimulate the proliferation of memory T cells. Relative to WT mice, influenza-infected CCR2-deficient mice display marked reductions in the accumulation of monocyte-derived inflammatory cells, cells producing NOS2, the expression of costimulatory molecules, markers of lung injury, weight loss, and mortality. We conclude that CCR2(+) monocyte-derived cells are the predominant cause of immune pathology during influenza infection and that such pathology is markedly abrogated in the absence of CCR2.
Lin
Kaifeng Lisa
KL
Department of Medicine, Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
Suzuki
Yasushi
Y
Nakano
Hideki
H
Ramsburg
Elizabeth
E
Gunn
Michael Dee
MD
D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005122:Exudates and Transudates / Q000276:immunology / Q000378:metabolism / Q000821:virology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000401:mortality* / Q000473:pathology*; D011024:Pneumonia, Viral / Q000276:immunology / Q000401:mortality* / Q000473:pathology*; D054390:Receptors, CCR2 / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2