Significance of IL-34 and SDC-1 in the pathogenesis of RA cells and preclinical models

Area of Science:

• Immunology
• Rheumatology
• Cell Biology

Background:

• Interleukin-34 (IL-34) interacts with M-CSF receptor and other receptors like protein-tyrosine phosphatase zeta (PTPζ) and syndecan-1 (SDC-1).
• IL-34 is crucial for Langerhans and microglial cell development physiologically, but implicated in rheumatoid arthritis (RA) pathogenesis via SDC-1.
• Elevated IL-34 correlates with RA disease markers like rheumatoid factor (RF), DAS28, ESR, and CRP, and radiographic progression.

Purpose of the Study:

• To investigate the role of IL-34 and its receptor SDC-1 in RA pathogenesis.
• To explore the therapeutic potential of targeting IL-34/SDC-1 signaling in preclinical RA models.

Main Methods:

• Analysis of IL-34 levels and correlation with RA disease markers.
• Investigating IL-34-induced macrophage reprogramming in RA using antibody therapies targeting M-CSFR or SDC-1.
• Utilizing IL-34 knockout (KO) and SDC-1 KO mice in collagen-induced arthritis (CIA) models.
• Assessing the impact of glucose uptake inhibition and genetic deficiencies on arthritis severity and immune cell function.

Main Results:

• IL-34 promotes RA by inducing glycolytic reprogramming of macrophages (CD14+CD86+GLUT1+).
• Therapies targeting M-CSFR or SDC-1, glucose uptake inhibition, or RAG deficiency mitigated inflammatory and erosive changes in arthritic mice.
• IL-34-/- and SDC-1-/- mice exhibited reduced CIA joint inflammation, osteoclast formation, and neovascularization, with suppressed monocyte infiltration and immune cell activation.

Conclusions:

• Targeting the IL-34/SDC-1 pathway disrupts the metabolic rewiring of myeloid and lymphoid cells in RA.
• Interfering with IL-34/SDC-1 signaling or related metabolites offers a unique strategy to intercept immune cell crosstalk in RA.
• This approach holds promise for novel therapeutic interventions in rheumatoid arthritis.