Phospholipase C gamma 2 is critical for development of a murine model of inflammatory arthritis by affecting actin dynamics in dendritic cells.
BACKGROUND
Dendritic cells (DCs) are highly specialized cells, which capture antigen in peripheral tissues and migrate to lymph nodes, where they dynamically interact with and activate T cells. Both migration and formation of DC-T cell contacts depend on cytoskeleton plasticity. However, the molecular bases governing these events have not been completely defined.


RESULTS
Utilizing a T cell-dependent model of arthritis, we find that PLCgamma2-/- mice are protected from local inflammation and bone erosion. PLCgamma2 controls actin remodeling in dendritic cells, thereby affecting their capacity to prime T cells. DCs from PLCgamma2-/- mice mature normally, however they lack podosomes, typical actin structures of motile cells. Absence of PLCgamma2 impacts both DC trafficking to the lymph nodes and migration towards CCL21. The interaction with T cells is also affected by PLCgamma2 deficiency. Mechanistically, PLCgamma2 is activated by CCL21 and modulates Rac activation. Rac1/2-/- DCs also lack podosomes and do not respond to CCL21. Finally, antigen pulsed PLCgamma2-/- DCs fail to promote T cell activation and induce inflammation in vivo when injected into WT mice. Conversely, injection of WT DCs into PLCgamma2-/- mice rescues the inflammatory response but not focal osteolysis, confirming the importance of PLCgamma2 both in immune and bone systems.


CONCLUSIONS
This study demonstrates a critical role for PLCgamma2 in eliciting inflammatory responses by regulating actin dynamics in DCs and positions the PLCgamma2 pathway as a common orchestrator of bone and immune cell functions during arthritis.
Cremasco
Viviana
V
Department of Orthopaedics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Benasciutti
Elisa
E
Cella
Marina
M
Kisseleva
Marina
M
Croke
Monica
M
Faccio
Roberta
R
D000199:Actins / Q000378:metabolism*; D000818:Animals; D001168:Arthritis / Q000201:enzymology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000378:metabolism; D015398:Signal Transduction
D000199:Actins; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D051966:Phospholipase C gamma