Impaired lung dendritic cell activation in CCR2 knockout mice.
Dendritic cell (DC) recruitment is a hallmark event in antigen (Ag)-challenged lungs. We previously reported models for analyzing DC migration and activation in the lung after Th1- or Th2-eliciting pathogen Ag-bead challenge. To determine the role of chemokines in DC mobilization, we applied this analysis to CCR1, CCR2, CCR5, and CCR6 chemokine receptor knockout mice. Both Mycobacteria bovis protein Ags and helminthic, Schistosoma mansoni egg Ags elicited multiple chemokines, including CCR1, CCR2, CCR5, and to a lesser extent CCR6 ligands. DCs from wild-type lungs expressed transcripts for chemokine receptors, CCR1, CCR2, CCR5, and CXCR4. In all knockout strains, CD11c+ cells were recruited to Ag-beads likely because of receptor redundancy. However, DCs in CCR2-/- mice had significantly decreased MHCII and CD40 expression. This was associated with abrogated cytokine production in draining lymph node cultures. Analysis of local innate inflammation revealed a 50% reduction in macrophage recruitment in CCR2-/- mice. Bone marrow chimeras of mixed CCR2+/+ green fluorescent protein transgenic and CCR2-/- green fluorescent protein-negative cells confirmed the DC maturation defect was only among the latter population. In conclusion, CCR2 knockout confers an intrinsic DC activation defect and CCR2 ligands likely promote the local activation/maturation of inflammatory DCs.
Department of Pathology, University of Michigan Medical School, Ann Arbor, USA.
Bo-Chin
BC
Chiu
Christine M
CM
Freeman
Valerie R
VR
Stolberg
Jerry S
JS
Hu
Kyriaki
K
Zeibecoglou
Bao
B
Lu
Craig
C
Gerard
Israel F
IF
Charo
Sergio A
SA
Lira
Stephen W
SW
Chensue
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D000947:Antigens, Helminth / Q000276:immunology; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology*; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D008168:Lung / Q000166:cytology* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000942:Antigens, Bacterial; D000947:Antigens, Helminth; D039521:CD11c Antigen; D019013:CD40 Antigens; C515301:Ccr1 protein, mouse; C515335:Ccr2 protein, mouse; D018925:Chemokines; D000949:Histocompatibility Antigens Class II; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine