CCR2 and CCR6, but not endothelial selectins, mediate the accumulation of immature dendritic cells within the lungs of mice in response to particulate antigen.
Dendritic cells (DC) migrate from sites of inflammation to lymph nodes to initiate primary immune responses, but the molecular mechanisms by which DC are replenished in the lungs during ongoing pulmonary inflammation are unknown. To address this question, we analyzed the secondary pulmonary immune response of Ag-primed mice to intratracheal challenge with the particulate T cell-dependent Ag sheep erythrocytes (SRBC). We studied wild-type C57BL/6 mice and syngeneic gene-targeted mice lacking either both endothelial selectins (CD62E and CD62P), or the chemokine receptors CCR2 or CCR6. DC, defined as non-autofluorescent, MHC class II(+)CD11c(mod) cells, were detected in blood, enzyme-digested minced lung, and bronchoalveolar lavage fluid using flow cytometry and immunohistology. Compared with control mice, Ag challenge increased the frequency and absolute numbers of DC, peaking at day 1 in peripheral blood (6.5-fold increase in frequency), day 3 in lung mince (20-fold increase in total DC), and day 4 in bronchoalveolar lavage fluid (55-fold increase in total DC). Most lung DC expressed CD11c, CD11b, and low levels of MHC class II, CD40, CD80, and CD86, consistent with an immature myeloid phenotype. DC accumulation depended in part upon CCR2 and CCR6, but not endothelial selectins. Thus, during lung inflammation, immature myeloid DC from the bloodstream replace emigrating immature DC and transiently increase total intrapulmonary APC numbers. Early DC recruitment depends in part on CCR2 to traverse vascular endothelium, plus CCR6 to traverse alveolar epithelium. The recruitment of circulating immature DC represents a potential therapeutic step at which to modulate immunological lung diseases.
Pulmonary and Critical Care Medicine Section, Medical Service, Department of Veterans Affairs Health System, 2215 Fuller Road, Ann Arbor, MI 48105, USA.
John J
JJ
Osterholzer
Theresa
T
Ames
Timothy
T
Polak
Joanne
J
Sonstein
Bethany B
BB
Moore
Stephen W
SW
Chensue
Galen B
GB
Toews
Jeffrey L
JL
Curtis
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019040:E-Selectin / Q000097:blood / Q000235:genetics / Q000502:physiology; D004912:Erythrocytes / Q000276:immunology*; D005260:Female; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000098:blood supply / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054390:Receptors, CCR2; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012756:Sheep
C498126:CCR6 protein, mouse; C515335:Ccr2 protein, mouse; D019040:E-Selectin; D054390:Receptors, CCR2; D054399:Receptors, CCR6; D019707:Receptors, Chemokine