Phospholipase C Gamma 2 Is Critical for Development of a Murine Model of Inflammatory Arthritis by Affecting Actin Dynamics in Dendritic Cells

Abstract

BackgroundDendritic 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 FindingsUtilizing a T cell-dependent model of arthritis, we find that PLCγ2−/− mice are protected from local inflammation and bone erosion. PLCγ2 controls actin remodeling in dendritic cells, thereby affecting their capacity to prime T cells. DCs from PLCγ2−/− mice mature normally, however they lack podosomes, typical actin structures of motile cells. Absence of PLCγ2 impacts both DC trafficking to the lymph nodes and migration towards CCL21. The interaction with T cells is also affected by PLCγ2 deficiency. Mechanistically, PLCγ2 is activated by CCL21 and modulates Rac activation. Rac1/2−/− DCs also lack podosomes and do not respond to CCL21. Finally, antigen pulsed PLCγ2−/− DCs fail to promote T cell activation and induce inflammation in vivo when injected into WT mice. Conversely, injection of WT DCs into PLCγ2−/− mice rescues the inflammatory response but not focal osteolysis, confirming the importance of PLCγ2 both in immune and bone systems.Conclusions/SignificanceThis study demonstrates a critical role for PLCγ2 in eliciting inflammatory responses by regulating actin dynamics in DCs and positions the PLCγ2 pathway as a common orchestrator of bone and immune cell functions during arthritis.

Targeted Inhibition of Phospholipase C γ2 Adaptor Function Blocks Osteoclastogenesis and Protects from Pathological Osteolysis

“…In vivo immune phenotypes caused by genetic alterations of Plc␥2 have been described. We and others (12)(13)(14) have shown that PLC␥2 regulates inflammation and autoimmunity, specifically within the bone microenvironment. Plc␥2 Ϫ/Ϫ mice are protected from immune activation in serum transfer arthritis and antigen-induced arthritis (13,14).…”

“…We and others (12)(13)(14) have shown that PLC␥2 regulates inflammation and autoimmunity, specifically within the bone microenvironment. Plc␥2 Ϫ/Ϫ mice are protected from immune activation in serum transfer arthritis and antigen-induced arthritis (13,14). In humans, a dominantly inherited disease called PLAID (PLC␥2-associated antibody deficiency and immune dysregulation) is caused by mutant alleles of PLC␥2 in which small, in-frame genomic deletions eliminate part or all of the C-terminal SH2 domain of PLC␥2.…”

“…However, the major limitation of these inhibitors is lack of specificity. Using a genetic model consisting of Plc␥2-deficient mice, we previously showed that PLC␥2 is required for the maintenance of basal bone mass and for protection from inflammatory arthritis (13)(14)(15). Thus, the goal of the current study was to identify a specific approach to target endogenous PLC␥2 function.…”

“…Plc␥2 Ϫ/Ϫ mice have increased bone mass (osteopetrosis) due to reduced differentiation of BMMs into OCs (15). Additionally, Plc␥2 Ϫ/Ϫ mice are protected from serum transfer-induced arthritis and antigen-induced arthritis due to functional defects in neutrophils and dendritic cells, respectively (13,14). Therefore, PLC␥2 is a promising target for therapeutic design in the context of inflammatory osteolysis.…”

Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass

“…We have reported that ablation of PLCγ2 results in a blockade of osteoclastogenesis owing to defective NFATc1 induction (11,22). PLCγ2-deficient mice are osteopetrotic and are also protected from inflammatory osteolysis (23,24). Therefore, we sought to identify novel PLCγ2-dependent signaling mediators that could inform therapeutic design for disorders caused by OC overactivity, such as osteoporosis and RA.…”