Journal List > J Rheum Dis > v.20(2) > 1064096

Kim: Phosphoinositide 3-kinase (PI3K) as a New Therapeutic Target for Rheumatoid Arthritis

Abstract

Dysregulated activation of immune and synovial cells and their reciprocal action play a key role in the pathogenesis of rheumatoid arthritis (RA). Various signal transduction molecules regulate cellular responses and small molecular inhibitors targeting the signal molecules, such as Janus kinase (JAK) and spleen tyrosine kinase (Syk) inhibitors, which have been developed for treating RA. Phosphoinositide 3-kinase (PI3K) is one of the signal molecules, which regulates innate and adaptive immune systems and is over-expressed in RA. PI3Ks phosphorylate phosphoinositide-4,5- bisphosphate (PI-4,5-P2) generates phosphoinositide-3,4,5- triphosphate (PI-3,4,5-P3) at the cell membrane. PI3Ks are divided into class I, II and III. Two catalytic subunits, p110γ and p110δ of PI3K, modulate cellular development, differentiation, proliferation, migration, cytokine synthesis and antibody production in both innate and adaptive immune systems. In RA synovium and synovial fibroblasts, the expression of p110γ and p110δ is increased, and their upregulation results in the abnormal activation of cellular immune responses. In preclinical animal models for RA, genetic deletion of p110γ and p110δ and selective inhibitors decrease the clinical arthritis score, synovial inflammation, cellular infiltration, bone and cartilage erosion and osteoclast activity. There is a synergistic effect for controlling arthritis by dual inhibition of PI3Kγ and PI3Kδ. Through reviewing the function of PI3K in the immune system and the effect of PI3K inhibition in preclinical arthritis animal models, we can expect the PI3K inhibition as a new therapeutic target for treatment of RA.

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Figure 1.
Simplified scheme of class I phosphoinositide 3-kinases (PI3Ks) and their intracellular cas-cades. Class IA PI3Ks are activated by tyrosine kinase receptor or by protein tyrosine kinase and class IB PI3K is recruited to G-protein- coupled receptor. After activation, class I PI3Ks phosphorylate phosphoinositide-4,5-bisphosphate (PI-4, 5-P2) to generate phosphoinositide 3,4,5-triphosphate (PI-3,4,5-P3) at cell membrane. The generation of PI-3,4,5-P3 activates downstream phosphorylation cascades, resulting in the induction of various cellular biologic functions.
jrd-20-74f1.tif
Table 1.
Classification of phosphoinositide 3-kinases (PI3Ks). Catalytic and regulatory subunits of PI3Ks and their substrates and products
  Catalytic subunit Regulatory subunit Substrate Product
Class IA        
  PI3Kα p110α      
  PI3Kβ p110β p85α, p50α, p55α, p85β, p55γ PI-4,5-P2 PIP3
  PI3Kδ p110δ      
Class IB        
  PI3Kγ p110γ p110, p84 PI-4,5-P2 PIP3
Class II PI3K-C2α   PI-4-P PI-3,4-P2
  PI3K-C2β   PI PI-3-P
  PI3K-C2δ      
Class III VPS34 p150 PI PI-3-P
Table 2.
The roles of PI3Kγ and PI3Kδ subunits on hematopoietic cells
  PI3Kγ PI3Kδ
T cell - Development of thymocytes - Maturation and differentiation into Th1, Th2, Th17 cells
  - Proliferation - Clonal expansion
  - Cytokine synthesis - Lymph node homing
  - Immunological synaps organization - Survival of Treg cell
    - T cell trafficking
B cell   - Development and maturation
    - Proliferation
    - Activation
    - Antibody production
    - Immunoglobulin switching
Neutrophil - Chemotaxis - Chemotaxis
  - Adhesion  
  - ROS production  
  - Cell polarization  
Macrophage/monocyte - Chemotaxis  
  - ROS production  
Mast cell - Degranulation (late phase) - Degranulation (early phase)
Eosinophil - Chemotaxis  
NK cell   - Chemotaxis
Table 3.
Preclinical animal models and the effect of specific inhibitors for the determination of PI3Kγ and PI3Kδ activity in rheumatoid arthritis
Targeted PI3K Method of PI3K inhibition Animal models Effect of PI3K inhibition
PI3Kγ Pik3cg−/− mice (50) α CII-induced arthritis - Very mild paw swelling with a reduced number of infiltrating cells
      - Less severe cartilage erosion
      - Low histopathological scores in synovial inflammation and cartilage erosion
      - Few neutrophil in the arthritic joints
PI3Kγ AS-605240 (50) Collagen-induced arthritis - Semitherapeutic protocol: mild arthritis with no increase in digit inflammation or paw thickness
      - Therapeutic protocol: reverted digit inflammation and paw thickness, reduced synovial inflammation and cartilage erosion, fewer infiltration of neutrophils in arthritic joints
PI3Kγ AS-605240 (50) α CII-induced arthritis - Reduced clinical and histological signs of joint inflammation
PI3Kγ p110γ−/− mice (51) K/BxN serum transfer model - Reduction in the extent of paw edema
      - Reduced LTB4-mediated neutrophil tissue accumulation
PI3Kγ p110γ−/− mice (53) hTNFtg mice - Reduced severity of arthritis
      - Less severe joint inflammation in histological analysis
      - Less formation of TRAP-positive synovial osteoclasts
      - Reduction of total cell number in synovial tissue
      - Less cartilage damage
      - Reduced MMP expression and invasive properties in synovial fibroblasts
PI3Kγ AS-605240 (52) Antigen-induced arthritis (AIA) - Marked decrease of clinical symptoms in early AIA
      - Diminished macrophage migration and activation
      - Impaired macrophage and neutrophil infiltration into the knee joint
PI3Kγ p110γ−/− mice (52) Antigen-induced arthritis (AIA) - Decrease of clinical symptoms in early AIA
      - Inhibited migration of macrophages towards C5a
      - Decreased activity of peritoneal macrophages
PI3Kδ IC87114 (54) Collagen-induced arthritis - Decrease of osteoclast formation
      - Inhibited bone resorption activity of osteoclasts
PI3Kδ p110δ−/− mice (51) K/BxN serum transfer model - Reduction in the extent of paw edema
      - Reduced LTB4-mediated neutrophil tissue accumulation
      - Slow migration velocity of neutrophils
PI3Kδ IC87114 (51) K/BxN serum transfer model - Reduction in the overall extent of inflammation and associated bone and cartilage erosion
PI3Kδ p110γδ−/− mice (51) K/BxN serum transfer model - Minimal paw swelling
      - Relatively normal articular surfaces, intact joint spaces, and absence of significant periarticular inflammation
      - Limited movement of neutrophils
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