Skin-derived macrophages from Leishmania major-susceptible mice exhibit interleukin-12- and interferon-γ-independent nitric oxide production and parasite killing after treatment with immunostimulatory DNA

Esther Von Stebut, Yasmine Belkaid, Bai Nguyen, Mark Wilson, David L. Sacks, Mark C. Udey

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Co-administration of CpG-containing immunostimulatory oligodeoxynucleotides and parasite antigen protects susceptible BALB/c mice from otherwise progressive infection with Leishmania major. Although the protective effect of CpG-containing immunostimulatory oligodeoxynucleotides is clearly dependent on endogenous interleukin-12 and interferon-γ production, the source of these Th1-promoting cytokines in infected mice is unknown. In contrast to macrophages from Leishmania-resistant C57BL/6 mice, macrophages from susceptible BALB/c mice are hyporesponsive to stimulation with lipopolysaccharide and interferon-γ. While studying interactions of various antigen-presenting cells with Leishmania, we found that BALB/c inflammatory skin macrophages, whether Leishmania-infected or uninfected, produced large amounts of interleukin-12 when treated with CpG-containing immunostimulatory oligodeoxynucleotides. Like lipopolysaccharide, CpG-containing immunostimulatory oligodeoxynucleotides induced production of interferon-γ and release of nitric oxide by skin macrophages. Studies using skin macrophages from interleukin-12- and interferon-γ-deficient BALB/c mice demonstrated that nitric oxide release was not dependent on interleukin-12 and interferon-γ production. Approximately 44% and 27% of intracellular Leishmania major amastigotes were killed by infected skin macrophages within 72 h upon stimulation with CpG-containing immunostimulatory oligodeoxynucleotides and lipopolysaccharide, respectively. Parasite killing by macrophages was independent of endogenous interferon-γ production, but was strongly enhanced by exogenous interferon-γ. Parasite elimination was dependent on the induction of nitric oxide, however. In vivo, injection of CpG-containing immunostimulatory oligodeoxynucleotides into lesional skin reduced the parasite burden ≈50-fold within the first 5 d of infection prior to full generation of a Th response. These results suggest that skin macrophages, constituting the principal reservoir of parasites in infected susceptible mice, produce Th1-promoting cytokines in response to CpG-containing immunostimulatory oligodeoxynucleotides. In addition, CpG-containing immunostimulatory oligodeoxynucleotides may also act locally on skin macrophages to facilitate Leishmania clearance by inducing nitric oxide production.

Original languageEnglish
Pages (from-to)621-628
Number of pages8
JournalJournal of Investigative Dermatology
Volume119
Issue number3
DOIs
StatePublished - Sep 2002

Keywords

  • CpG motif
  • Cytokines
  • Leishmania
  • Macrophages
  • Monocytes
  • Nitric oxide

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