Impaired Lung Dendritic Cell Activation in CCR2 Knockout Mice

Abstract

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 Agbeads 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.

Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2–/– mice

“…The delayed recruitment of CD4 ϩ T cells to the lungs is consistent with impaired trafficking of CD4 ϩ and CD8 ϩ T cells to the site of inflammation in corona virus-infected CCR2Ϫ/Ϫ mice [20]. Immature DC from CCR2Ϫ/Ϫ mice exhibit defective maturation with significantly decreased MHC Class II and CD40 expression [44]. This may potentially result in impaired activation of CD4 ϩ T cells in CCR2Ϫ/Ϫ mice.…”

CCR2 and CCR6, but Not Endothelial Selectins, Mediate the Accumulation of Immature Dendritic Cells within the Lungs of Mice in Response to Particulate Antigen

“…Although recruitment was interpreted to be the major mechanism for changes in cell number in that study, a separate analysis of lung inflammation in response to Ag-coated beads identified an additional defect in maturation (i.e., up-regulation of MHC class II and CD40) in CD11c ϩ cells in CCR2 Ϫ/Ϫ mice (35). The differences in the methods used to identify DC precludes direct comparison of those results with the current data.…”

“…iDC bind E-and P-selectins under shear stress (15), making this adhesive system a plausible requirement for their recruitment. The second class of potential recruitment molecules were the chemokine receptors CCR2 and CCR6, which have recently been implicated in DC recruitment to the lung (19,34,35), tonsils (36,37), and injured skin (36 -38). Our results demonstrate that, in response to a single Ag challenge, the frequency of DC within peripheral blood increased rapidly, followed by a marked accumulation of DC within the lung interstitium and subsequently in the alveolar spaces.…”

Severe Sepsis Exacerbates Cell-Mediated Immunity in the Lung Due to an Altered Dendritic Cell Cytokine Profile

“…14,15,44 Immature DCs capture antigen in the peripheral tissue and migrate to the draining lymph nodes, where they activate T cells, and initiate the type-1 or type-2 immune response depending on the presence of IL-12 32,33 or IL-4, 32 respectively. Controversy surrounds the origin of DCs, subsets, and functional differences between subsets, despite considerable recent focus on DC biology.…”