Targeting of Phospholipase D1 Ameliorates Collagen-Induced Arthritis via Modulation of Treg and Th17 Cell Imbalance and Suppression of Osteoclastogenesis.

Hyun Jung Yoo,Won Chan Hwang,Do Sik Min

doi:10.3390/ijms21093230

Abstract

Phospholipase D1 (PLD1) plays a crucial role in various inflammatory and autoimmune diseases. Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease. However, the role of PLD1 in the pathogenesis of RA remains unknown. Here, we first investigated the role and effects of PLD1 in collagen-induced arthritis (CIA) and found that genetic and pharmacological inhibition of PLD1 in DBA1/J mice with CIA reduced the incidence of CIA, decreased the clinical score, and abrogated disease symptoms including infiltration of leukocytes, synovial inflammation, bone erosion, and cartilage destruction. Moreover, ablation and inhibition of PLD1 suppressed the production of type II collagen-specific IgG2a autoantibody and proinflammatory cytokines, accompanied by an increase in the regulatory T (Treg) cell population and a decrease in the Th17 cell population in CIA mice. The PLD1 inhibitor also promoted differentiation of Treg cells and suppressed differentiation of Th17 cells in vitro. Furthermore, the PLD1 inhibitor attenuated pathologic bone destruction in CIA mice by suppressing osteoclastogenesis and bone resorption. Thus, our findings indicate that the targeting of PLD1 can ameliorate CIA by modulating the imbalance of Treg and Th17 cells and suppressing osteoclastogenesis, which might be a novel strategy to treat autoimmune diseases, such as RA.

Highlights

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disorder that progressively destroys the articular cartilage and bones of the joints [1]
We investigated whether Phospholipase D1 (PLD1) could play a role in collagen-induced arthritis (CIA), using the CIA mouse that mimics many features of human RA
PLD1 has been reported to be upregulated in IL-15-induced RA synovial fibroblasts (RASF), IL-1β-stimulated synoviocytes, and synovia from patients with RA [14,30,31], the functional role of PLD1 in systemic bone destruction in RA remains poorly defined

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disorder that progressively destroys the articular cartilage and bones of the joints [1] Both environmental and genetic factors are involved in the etiology of RA, the precise mechanism of onset remains unclear. PLD1 has been reported to play an important role in Treg differentiation and T-cell activation [17,18,19,20]. It remains unknown whether targeting of PLD1 could affect the pathogenesis of RA via modulation of Treg/Th17 imbalance in the CIA model. We investigated the effects and molecular mechanisms of PLD1 in CIA using PLD1 knockout mice and the PLD1-selective inhibitor, VU0155069 [21]

Methods

Results

Conclusion