TY - JOUR
T1 - Effective clearance of intracellular Leishmania major in vivo requires pten in macrophages
AU - Kuroda, Shoko
AU - Nishio, Miki
AU - Sasaki, Takehiko
AU - Horie, Yasuo
AU - Kawahara, Koichi
AU - Sasaki, Masato
AU - Natsui, Miyuki
AU - Matozaki, Takashi
AU - Tezuka, Hiroyuki
AU - Ohteki, Toshiaki
AU - Förster, Irmgard
AU - Wak, Tak W.
AU - Nakano, Toru
AU - Suzuki, Akira
PY - 2008/5
Y1 - 2008/5
N2 - 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.
AB - 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.
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U2 - 10.1002/eji.200737302
DO - 10.1002/eji.200737302
M3 - Article
C2 - 18398930
AN - SCOPUS:47049086825
SN - 0014-2980
VL - 38
SP - 1331
EP - 1340
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 5
ER -