Cathepsin E-deficient mice show increased susceptibility to bacterial infection associated with the decreased expression of multiple cell surface Toll-like receptors.
Cathepsin E, an intracellular aspartic proteinase, is predominantly localized in the endosomal compartments of immune system cells. In the present study, we investigated the role of cathepsin E in immune defense systems against bacterial infection. Cathepsin E-deficient (CatE(-/-)) mice showed dramatically increased susceptibility to infection with both the Gram-positive bacterium Staphyrococcus aureus, and the Gram-negative bacterium Porphyromonas gingivalis when compared with syngeneic wild-type mice, most likely due to impaired regulation of bacterial elimination. Peritoneal macrophages from CatE(-/-) mice showed significantly impaired tumor necrosis factor-alpha and IL-6 production in response to S. aureus and decreased bactericidal activities toward this bacterium. Moreover, the cell surface levels of Toll-like receptor-2 (TLR2) and TLR4, which recognize specific components of Gram-positive and -negative bacteria, respectively, were decreased in CatE(-/-) macrophages, despite no significant difference in the total cellular expression levels of these receptors between the wild-type and CatE(-/-) macrophages, implying trafficking defects in these surface receptors in the latter. These results indicate an essential role of cathepsin E in immune defense against invading microorganisms, most probably due to regulation of the cell surface expression of TLR family members required for innate immune responses.
Tsukuba
Takayuki
T
Departments of Pharmacology, Pediatric Dentistry, and Fixed Prosthodontics, Graduate School of Dental Science, Kyushu University, Fukuoka 812-8582.
Yamamoto
Shinya
S
Yanagawa
Michiyo
M
Okamoto
Kuniaki
K
Okamoto
Yoshiko
Y
Nakayama
Keiichi I
KI
Kadowaki
Tomoko
T
Yamamoto
Kenji
K
D000818:Animals; D001424:Bacterial Infections / Q000209:etiology*; D020059:Cathepsin E / Q000172:deficiency*; D020022:Genetic Predisposition to Disease; D015850:Interleukin-6 / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport / Q000235:genetics; D013203:Staphylococcal Infections / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015850:Interleukin-6; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D020059:Cathepsin E