CCR2 plays a critical role in dendritic cell maturation: Possible role of CCL2 and NF-κB

Fabio Jimenez, Marlon P. Quinones, Hernan G. Martinez, Carlos A. Estrada, Kassandra Clark, Edgar Garavito, Jessica Ibarra, Peter C. Melby, Seema S. Ahuja

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

We postulated that CCR2-driven activation of the transcription factor NF-κB 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-κB 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-γ 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-κB in the regulation of DC/LC maturation processes that regulate protective immunity against intracellular pathogens.

Original languageEnglish (US)
Pages (from-to)5571-5581
Number of pages11
JournalJournal of Immunology
Volume184
Issue number10
DOIs
StatePublished - May 15 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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