Effective clearance of intracellular Leishmania major in vivo requires pten in macrophages

Shoko Kuroda, Miki Nishio, Takehiko Sasaki, Yasuo Horie, Koichi Kawahara, Masato Sasaki, Miyuki Natsui, Takashi Matozaki, Hiroyuki Tezuka, Toshiaki Ohteki, Irmgard Förster, Tak W. Wak, Toru Nakano, Akira Suzuki

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Abstract

Leishmaniases are a major international public health problem, and macrophages are crucial for host resistance to this parasite. To determine if phosphatase and tensin homologue deleted on chromosome ten (Pten), a negative regulator of the PI3K pathway, plays a role in macrophage-mediated resistance to Leishmania, we generated C57BL/6 mice lacking Pten specifically in macrophages (LysMCrePtenflox/flox mice). Examination of lesions resulting from Leishmania major infection showed that LysMCrePtenflox/flox mice were more susceptible to the parasite than wild-type (WT) mice in the early phase of the infection, but were eventually able to eliminate the pathogen. In vitro Pten-deficient macrophages showed a reduced ability to kill parasites in response to IFN-γ treatment, possibly because the mutant cells exhibited decreased TNF secretion that correlated with reductions in inducible nitric oxide synthase expression and nitric oxide production. In response to various TLR ligands, Pten-deficient macrophages produced less TNF and IL-12 but more IL-10 than WT cells. However, analysis of cells in the lymph nodes draining L. major inoculation sites indicated that both LysMCrePtenflox/flox and WT mice developed normal Th1 responses following L. major infection, in line with the ability of LysMCrePtenflox/flox mice to eventually eliminate the parasite. Our results indicate that the efficient clearance of intracellular parasites requires Pten in macrophages.

Original languageEnglish
Pages (from-to)1331-1340
Number of pages10
JournalEuropean Journal of Immunology
Volume38
Issue number5
DOIs
Publication statusPublished - 01-05-2008

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Kuroda, S., Nishio, M., Sasaki, T., Horie, Y., Kawahara, K., Sasaki, M., Natsui, M., Matozaki, T., Tezuka, H., Ohteki, T., Förster, I., Wak, T. W., Nakano, T., & Suzuki, A. (2008). Effective clearance of intracellular Leishmania major in vivo requires pten in macrophages. European Journal of Immunology, 38(5), 1331-1340. https://doi.org/10.1002/eji.200737302