TY - JOUR
T1 - Phosphatidylinositol 3-kinase, phosphoinositide-specific phospholipase-Cγ and protein kinase-C signal myelin phagocytosis mediated by complement receptor-3 alone and combined with scavenger receptor-AI/II in macrophages
AU - Makranz, Chen
AU - Cohen, Goni
AU - Baron, Ayellet
AU - Levidor, Lital
AU - Kodama, Tatsuhiko
AU - Reichert, Fanny
AU - Rotshenker, Shlomo
PY - 2004/3
Y1 - 2004/3
N2 - Complement-receptor-3 (CR3/MAC-1), scavenger-receptor-AI/II (SRAI/II) and Fcγ-receptor (FcγR) can mediate phagocytosis of degenerated myelin in macrophages and microglia. However, CR3/MAC-1 and SRAI/II, but not FcγR, mediate phagocytosis after axonal injury. We tested for phosphatidylinositol 3-kinase (PI3K), phosphoinositide-specific phospholipase-Cγ (PLCγ) and protein kinase-C (PKC) signaling in myelin phagocytosis mediated by CR3/MAC-1 alone and by CR3/MAC-1 combined with SRAI/II. Phagocytosis was inhibited by PI3K inhibitors wortmannin and LY-294002, PLCγ inhibitor U-73122, classical PKC (cPKC) inhibitor Go-6976, general PKC inhibitors Ro-318220 and calphostin-C, and BAPTA/AM which chelates intracellular Ca2+ required for cPKC activation. PKC activator PMA augmented phagocytosis and further alleviated inhibitions induced by PI3K and PLCγ inhibitors. Overall, altering PKC activity modulated phagocytosis 4- to 6-fold between inhibition and augmentation. PLCγ activation did not require tyrosine phosphorylation. Thus, signaling of myelin phagocytosis mediated by CR3/MAC-1 alone and by CR3/MAC-1 combined with SRAI/II involves PI3K, PLCγ and cPKC, the cascade PI3K→PLCγ→cPKC, and wide-range modulation by PKC. This pathway may thus be targeted for in vivo modulation, which may explain differences in the efficiency of CR3/MAC-1-mediated myelin phagocytosis in different pathological conditions.
AB - Complement-receptor-3 (CR3/MAC-1), scavenger-receptor-AI/II (SRAI/II) and Fcγ-receptor (FcγR) can mediate phagocytosis of degenerated myelin in macrophages and microglia. However, CR3/MAC-1 and SRAI/II, but not FcγR, mediate phagocytosis after axonal injury. We tested for phosphatidylinositol 3-kinase (PI3K), phosphoinositide-specific phospholipase-Cγ (PLCγ) and protein kinase-C (PKC) signaling in myelin phagocytosis mediated by CR3/MAC-1 alone and by CR3/MAC-1 combined with SRAI/II. Phagocytosis was inhibited by PI3K inhibitors wortmannin and LY-294002, PLCγ inhibitor U-73122, classical PKC (cPKC) inhibitor Go-6976, general PKC inhibitors Ro-318220 and calphostin-C, and BAPTA/AM which chelates intracellular Ca2+ required for cPKC activation. PKC activator PMA augmented phagocytosis and further alleviated inhibitions induced by PI3K and PLCγ inhibitors. Overall, altering PKC activity modulated phagocytosis 4- to 6-fold between inhibition and augmentation. PLCγ activation did not require tyrosine phosphorylation. Thus, signaling of myelin phagocytosis mediated by CR3/MAC-1 alone and by CR3/MAC-1 combined with SRAI/II involves PI3K, PLCγ and cPKC, the cascade PI3K→PLCγ→cPKC, and wide-range modulation by PKC. This pathway may thus be targeted for in vivo modulation, which may explain differences in the efficiency of CR3/MAC-1-mediated myelin phagocytosis in different pathological conditions.
KW - Axonal injury
KW - Complement-receptor-3
KW - Macrophage
KW - Microglia
KW - Myelin
KW - Phagocytosis
KW - Phosphatidylinositol 3-kinase (PI3K)
KW - Phospholipase-C (PLC)
KW - Protein kinase-C (PKC)
KW - Scavenger-receptor-AI/II
KW - Wallerian degeneration
UR - http://www.scopus.com/inward/record.url?scp=1542270757&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2003.11.007
DO - 10.1016/j.nbd.2003.11.007
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C2 - 15006698
AN - SCOPUS:1542270757
SN - 0969-9961
VL - 15
SP - 279
EP - 286
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 2
ER -
