CCR2 plays a critical role in dendritic cell maturation: possible role of CCL2 and NF-kappa B.
We postulated that CCR2-driven activation of the transcription factor NF-kappaB plays a critical role in dendritic cell (DC) maturation (e.g., migration, costimulation, and IL-12p70 production), necessary for the generation of protective immune responses against the intracellular pathogen Leishmania major. Supporting this notion, we found that CCR2, its ligand CCL2, and NF-kappaB were required for CCL19 production and adequate Langerhans cell (LC) migration both ex vivo and in vivo. Furthermore, a role for CCR2 in upregulating costimulatory molecules was indicated by the reduced expression of CD80, CD86, and CD40 in Ccr2(-/-) bone marrow-derived dendritic cells (BMDCs) compared with wild-type (WT) BMDCs. Four lines of evidence suggested that CCR2 plays a critical role in the induction of protective immunity against L. major by regulating IL-12p70 production and migration of DC populations such as LCs. First, compared with WT, Ccr2(-/-) lymph node cells, splenocytes, BMDCs, and LCs produced lower levels of IL-12p70 following stimulation with LPS/IFN-gamma or L. major. Second, a reduced number of LCs carried L. major from the skin to the draining lymph nodes in Ccr2(-/-) mice compared with WT mice. Third, early treatment with exogenous IL-12 reversed the susceptibility to L. major infection in Ccr2(-/-) mice. Finally, disruption of IL-12p70 in radioresistant cells, such as LCs, but not in BMDCs resulted in the inability to mount a fully protective immune response in bone marrow chimeric mice. Collectively, our data point to an important role for CCR2-driven activation of NF-kappaB in the regulation of DC/LC maturation processes that regulate protective immunity against intracellular pathogens.
Jimenez
Fabio
F
Audie L. Murphy Division, Veterans Administration Center for Research on AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
Quinones
Marlon P
MP
Martinez
Hernan G
HG
Estrada
Carlos A
CA
Clark
Kassandra
K
Garavito
Edgar
E
Ibarra
Jessica
J
Melby
Peter C
PC
Ahuja
Seema S
SS
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D007801:Langerhans Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D018448:Models, Immunological; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D054390:Receptors, CCR2 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D015533:Transcriptional Activation / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016328:NF-kappa B; D054390:Receptors, CCR2; D018664:Interleukin-12
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