Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice.
Nitric oxide (NO) and peroxynitrite, which are produced by activated microglia, are responsible for accelerated neurodegeneration in cathepsin D-deficient (CD-/-) mice. To elucidate the mechanisms by which microglia are initially activated in CD-/- mice, we analyzed the possible relationship between lysosomal storage and microglial activation. In CD-/- mice, the microglial NO-generating activity that was closely associated with the induction of inducible NO synthase and the cationic amino acid transporter-2 (CAT-2) coincided well with the lysosomal storage of subunit c of mitochondrial F0F1ATPase and the formation of ceroid/lipofuscin. Furthermore, activated microglia, which are often accumulating subunit c and ceroid/lipofuscin, showed proliferation activity and an activation of p38 mitogen-activated protein (MAP) kinase. In the primary cultured microglia, pepstatin A was found to enhance the generation of NO and superoxide anion radicals. In these pepstatin A-treated microglia, both an increased generation of the intracellular reactive oxygen species (ROS) and an activation of p38 MAP kinase were observed. These results suggest that the ceroid/lipofuscin which form in microglia activate the p38 MAP kinase cascade through the increased intracellular generation of ROS in CD-/- mice. The activated p38 MAP kinase cascade then promotes the expression of iNOS and CAT-2, thereby inducing the overproduction of NO.
Yamasaki
Ryo
R
Laboratory of Oral Aging Science, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Zhang
Jian
J
Koshiishi
Ichiro
I
Sastradipura Suniarti
Dewi F
DF
Wu
Zhou
Z
Peters
Christoph
C
Schwake
Michael
M
Uchiyama
Yasuo
Y
Kira
Jun-Ichi
J
Saftig
Paul
P
Utsumi
Hideo
H
Nakanishi
Hiroshi
H
D000818:Animals; D001124:Argininosuccinate Synthase / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism*; D027202:Cationic Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D048430:Cell Shape; D002478:Cells, Cultured; D004789:Enzyme Activation; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010436:Pepstatins / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D027202:Cationic Amino Acid Transporter 2; D010436:Pepstatins; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases; D002402:Cathepsin D; D001124:Argininosuccinate Synthase; C031375:pepstatin