Phospholipase Cgamma2 mediates RANKL-stimulated lymph node organogenesis and osteoclastogenesis.
Phospholipase Cgamma2 (PLCgamma2) is an important signaling effector of multiple receptors in the immune system. Here we show that PLCgamma2-deficient mice displayed impaired lymph node organogenesis but normal splenic structure and Peyer's patches. Receptor activator of NF-kappaB ligand (RANKL) is a tumor necrosis factor family cytokine and is essential for lymph node organogenesis. Importantly, PLCgamma2 deficiency severely impaired RANKL signaling, resulting in marked reduction of RANKL-induced activation of MAPKs, p38 and JNK, but not ERK. The lack of PLCgamma2 markedly diminished RANKL-induced activation of NF-kappaB, AP-1, and NFATc1. Moreover, PLCgamma2 deficiency impaired RANKL-mediated biological function, leading to failure of the PLCgamma2-deficient bone marrow macrophage precursors to differentiate into osteoclasts after RANKL stimulation. Re-introduction of PLCgamma2 but not PLCgamma1 restores RANKL-mediated osteoclast differentiation of PLCgamma2-deficient bone marrow-derived monocyte/macrophage. Taken together, PLCgamma2 is essential for RANK signaling, and its deficiency leads to defective lymph node organogenesis and osteoclast differentiation.
Chen
Yabing
Y
Department of Pathology, University of Alabama at Birmingham and Veterans Affairs Medical Center, Birmingham, Alabama 35294, USA.
Wang
Xiaohong
X
Di
Lie
L
Fu
Guoping
G
Chen
Yuhong
Y
Bai
Li
L
Liu
Jianzhong
J
Feng
Xu
X
McDonald
Jay M
JM
Michalek
Sue
S
He
Yinghong
Y
Yu
Mei
M
Fu
Yang-Xin
YX
Wen
Renren
R
Wu
Hui
H
Wang
Demin
D
D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D038081:Organogenesis; D010010:Osteoclasts / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism / Q000502:physiology*; D053245:RANK Ligand / Q000502:physiology*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D053245:RANK Ligand; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051966:Phospholipase C gamma