Epigenetic Regulation Of Dendritic Cell Migration

Abstract

RationaleThe chemokine receptor CCR7 is critically important for the trafficking of lung dendritic cells (DCs) to lymph nodes (LN), where they orchestrate the development of allergic responses to inhaled allergens. Our objective was to investigate the molecular mechanisms that regulate lineage-specific CCR7 expression in DCs.MethodsCcr7 expression and function was evaluated in conventional DCs (cDCs) and monocyte-derived DCs (moDCs) generated from bone marrow (BM) of wild type or Ccr7(gfp) reporter mice. Chromatin immunoprecipitation assays were performed to assess epigenetic modifications of the Ccr7 locus in BM-derived DCs, primary lung DC subsets and progenitor populations.ResultsBM-derived cDCs expressed Ccr7 following activation with lipopolysaccharide and migrated efficiently to CCR7 ligands both in vitro and in vivo. By contrast, BM-derived moDCs did not express Ccr7 or respond to CCR7 ligands. The Ccr7 promoter in BM-derived moDCs was enriched for the transcriptionally repressive histone modification H3K27 tri-methylation, consistent with epigenetic regulation of gene expression. In the lung, similar repressive histone modifications at the Ccr7 locus were detected in CD11b(hi)Ly-6C(hi) moDCs, but not in migratory CD103+ cDCs. Furthermore, progenitors for lung cDCs and moDCs had disparate levels of H3K27 tri-methylation at the Ccr7 promoter, indicating that epigenetic regulation of Ccr7 occurs early during DC lineage commitment.ConclusionsLineage-specific epigenetic mechanisms regulate CCR7-dependent DC migration, and thus help dictate the functional role of DC subsets. Manipulating epigenetic pathways could provide a novel strategy for the improvement of DC-based immunotherapies and the treatment of allergic diseases. RationaleThe chemokine receptor CCR7 is critically important for the trafficking of lung dendritic cells (DCs) to lymph nodes (LN), where they orchestrate the development of allergic responses to inhaled allergens. Our objective was to investigate the molecular mechanisms that regulate lineage-specific CCR7 expression in DCs. The chemokine receptor CCR7 is critically important for the trafficking of lung dendritic cells (DCs) to lymph nodes (LN), where they orchestrate the development of allergic responses to inhaled allergens. Our objective was to investigate the molecular mechanisms that regulate lineage-specific CCR7 expression in DCs. MethodsCcr7 expression and function was evaluated in conventional DCs (cDCs) and monocyte-derived DCs (moDCs) generated from bone marrow (BM) of wild type or Ccr7(gfp) reporter mice. Chromatin immunoprecipitation assays were performed to assess epigenetic modifications of the Ccr7 locus in BM-derived DCs, primary lung DC subsets and progenitor populations. Ccr7 expression and function was evaluated in conventional DCs (cDCs) and monocyte-derived DCs (moDCs) generated from bone marrow (BM) of wild type or Ccr7(gfp) reporter mice. Chromatin immunoprecipitation assays were performed to assess epigenetic modifications of the Ccr7 locus in BM-derived DCs, primary lung DC subsets and progenitor populations. ResultsBM-derived cDCs expressed Ccr7 following activation with lipopolysaccharide and migrated efficiently to CCR7 ligands both in vitro and in vivo. By contrast, BM-derived moDCs did not express Ccr7 or respond to CCR7 ligands. The Ccr7 promoter in BM-derived moDCs was enriched for the transcriptionally repressive histone modification H3K27 tri-methylation, consistent with epigenetic regulation of gene expression. In the lung, similar repressive histone modifications at the Ccr7 locus were detected in CD11b(hi)Ly-6C(hi) moDCs, but not in migratory CD103+ cDCs. Furthermore, progenitors for lung cDCs and moDCs had disparate levels of H3K27 tri-methylation at the Ccr7 promoter, indicating that epigenetic regulation of Ccr7 occurs early during DC lineage commitment. BM-derived cDCs expressed Ccr7 following activation with lipopolysaccharide and migrated efficiently to CCR7 ligands both in vitro and in vivo. By contrast, BM-derived moDCs did not express Ccr7 or respond to CCR7 ligands. The Ccr7 promoter in BM-derived moDCs was enriched for the transcriptionally repressive histone modification H3K27 tri-methylation, consistent with epigenetic regulation of gene expression. In the lung, similar repressive histone modifications at the Ccr7 locus were detected in CD11b(hi)Ly-6C(hi) moDCs, but not in migratory CD103+ cDCs. Furthermore, progenitors for lung cDCs and moDCs had disparate levels of H3K27 tri-methylation at the Ccr7 promoter, indicating that epigenetic regulation of Ccr7 occurs early during DC lineage commitment. ConclusionsLineage-specific epigenetic mechanisms regulate CCR7-dependent DC migration, and thus help dictate the functional role of DC subsets. Manipulating epigenetic pathways could provide a novel strategy for the improvement of DC-based immunotherapies and the treatment of allergic diseases. Lineage-specific epigenetic mechanisms regulate CCR7-dependent DC migration, and thus help dictate the functional role of DC subsets. Manipulating epigenetic pathways could provide a novel strategy for the improvement of DC-based immunotherapies and the treatment of allergic diseases.