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. Methodology/Principal Findings: Utilizing a T cell-dependent model of arthritis, we find that PLC gamma 2-/- mice are protected from local inflammation and bone erosion. PLC gamma 2 controls actin remodeling in dendritic cells, thereby affecting their capacity to prime T cells. DCs from PLC gamma 2-/- mice mature normally, however they lack podosomes, typical actin structures of motile cells. Absence of PLC gamma 2 impacts both DC trafficking to the lymph nodes and migration towards CCL21. The interaction with T cells is also affected by PLC gamma 2 deficiency. Mechanistically, PLC gamma 2 is activated by CCL21 and modulates Rac activation. Rac1/2-/- DCs also lack podosomes and do not respond to CCL21. Finally, antigen pulsed PLC gamma 2-/- DCs fail to promote T cell activation and induce inflammation in vivo when injected into WT mice. Conversely, injection of WT DCs into PLC gamma 2-/- mice rescues the inflammatory response but not focal osteolysis, confirming the importance of PLC gamma 2 both in immune and bone systems. Conclusions/Significance: This study demonstrates a critical role for PLC gamma 2 in eliciting inflammatory responses by regulating actin dynamics in DCs and positions the PLC gamma 2 pathway as a common orchestrator of bone and immune cell functions during arthritis.