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Published on: April 11, 2018
Impact of JAK-inhibition on pain and biphasic P2X7R expression on CD4+ T cells in experimental arthritis
Jérôme Biton1,2, Roxane Hervé1,2, Magali Breckler1,2
1Inserm U1125, UFR SMBH, 1 rue de Chablis, 93000, Bobigny, France.
Abstract:
Pain improvement is a major unmet need for patients with rheumatoid arthritis (RA). The purinergic receptor P2 X7R may play a central role in inflammatory pain. We aimed to assess the differential effect of Jak and TNF-α inhibition on pain in a collagen-induced arthritis (CIA) mouse model and to decipher mechanisms, focusing on P2X7R. Either a Jak-inhibitor (baricitinib, BARI) or an anti-TNF-α (etanercept, ETN) were administered to CIA mice in early or late phase of arthritis. Pain was evaluated with three independent tests. We assessed P2X7R on leucocytes and IFN-γ, IL-1β, TNF-α, IL-10, IL-6 and IL-17 A concentrations. BARI and ETN decreased joint inflammation and ameliorated histologic destruction and inflammation. When administered in the late phase, ETN and BARI exerted an analgesic effect. P2X7R expression on blood CD4+ T cells was increased in early phase BARI treated mice, and decreased in late phase. When treatments were administered early, percentage of P2 × 7R+ CD4+ T cells inversely correlated with clinical and histological scores, and with IL-6, IL-17 A and IL-1β levels. In conclusion, both BARI and ETN improved pain in a CIA model. The differential expression of P2X7R on CD4+ T cells according to the time of BARI administration may contribute to a better understanding of pain mechanisms in arthritis.
Insights
Rheumatoid arthritis pain was improved by baricitinib (JAK inhibitor) and etanercept (TNF-α inhibitor) in a mouse model. These treatments differentially affected P2X7R expression on T cells, offering insights into pain mechanisms.
Area of Science:
- Immunology
- Pharmacology
- Rheumatology
Background:
- Rheumatoid arthritis (RA) poses significant unmet needs for pain management.
- The purinergic receptor P2X7R is implicated in inflammatory pain pathways.
- Understanding pain mechanisms in RA is crucial for developing effective therapies.
Purpose of the Study:
- To evaluate the impact of JAK inhibition (baricitinib) and TNF-α inhibition (etanercept) on pain in a collagen-induced arthritis (CIA) mouse model.
- To investigate the role of P2X7R in mediating pain relief under these therapeutic interventions.
- To explore the differential effects based on the timing of treatment administration (early vs. late phase of arthritis).
Main Methods:
- Administration of baricitinib or etanercept to CIA mice during early or late stages of arthritis.
- Pain assessment using three independent behavioral tests.
- Flow cytometry analysis of P2X7R expression on leukocytes, specifically CD4+ T cells.
- Measurement of cytokine concentrations (IFN-γ, IL-1β, TNF-α, IL-10, IL-6, IL-17A).
Main Results:
- Both baricitinib and etanercept reduced joint inflammation, histological damage, and pain, particularly when administered in the late phase of arthritis.
- P2X7R expression on CD4+ T cells showed dynamic changes: increased with early baricitinib treatment and decreased with late-phase treatment.
- Early treatment with baricitinib demonstrated an inverse correlation between P2X7R+ CD4+ T cells and clinical/histological scores, as well as IL-6, IL-17A, and IL-1β levels.
Conclusions:
- Baricitinib and etanercept effectively alleviate pain in a collagen-induced arthritis mouse model.
- The time-dependent modulation of P2X7R expression on CD4+ T cells by baricitinib provides novel insights into arthritis pain mechanisms.
- Targeting JAK and TNF-α pathways, with consideration for P2X7R involvement, represents a promising strategy for managing pain in rheumatoid arthritis.
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