Effective clearance of intracellular Leishmania major in vivo requires Pten in macrophages.
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 (LysMCrePten(flox/flox) mice). Examination of lesions resulting from Leishmania major infection showed that LysMCrePten(flox/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-gamma 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 LysMCrePten(flox/flox) and WT mice developed normal Th1 responses following L. major infection, in line with the ability of LysMCrePten(flox/flox) mice to eventually eliminate the parasite. Our results indicate that the efficient clearance of intracellular parasites requires Pten in macrophages.
Kuroda
Shoko
S
Department of Molecular Biology, Akita University Graduate School of Medicine, Akita, Japan.
Nishio
Miki
M
Sasaki
Takehiko
T
Horie
Yasuo
Y
Kawahara
Koichi
K
Sasaki
Masato
M
Natsui
Miyuki
M
Matozaki
Takashi
T
Tezuka
Hiroyuki
H
Ohteki
Toshiaki
T
Förster
Irmgard
I
Mak
Tak W
TW
Nakano
Toru
T
Suzuki
Akira
A
D000818:Animals; D001119:Arginase / Q000378:metabolism; D004198:Disease Susceptibility / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D017353:Gene Deletion; D015870:Gene Expression / Q000187:drug effects; D019426:Integrases / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology; D018320:Leishmania major / Q000276:immunology* / Q000378:metabolism; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000469:parasitology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009573:Nitrites / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D007378:Interleukins; D009573:Nitrites; D018129:Phosphatidylinositol Phosphates; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C060974:phosphatidylinositol 3,4,5-triphosphate; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D009113:Muramidase; C472450:lysozyme M, mouse; D001119:Arginase