CX3CR1+ synovial macrophages accumulate in the joint during experimental hemophilic arthropathy but are not required for acute synovitis.

BACKGROUND

Hemophilic arthropathy (HA) is a chronic joint disease caused by repeated joint bleeding in patients with hemophilia, leading to joint degeneration despite prophylactic treatment. The CX3CL1 (fractalkine)-CX3CR1 chemokine axis regulates synovial lining macrophage function and has been implicated in inflammatory joint diseases including rheumatoid arthritis and osteoarthritis.

OBJECTIVES

This present study sought to assess the functional role of CX3CR1+ macrophages in experimental HA using genetic targeting and pharmacologic inhibition.

METHODS

We used factor (F)VIII-deficient mice (F8em1-/-) to model HA through subpatellar needle injury. Functional studies used dual F8em1-/-Cx3cr1-/- knockout mice and the CX3CR1 noncompetitive allosteric antagonist AZD8797. Outcomes were measured by changes in joint swelling after injury and histologic assessment at day 28 after injury for hemosiderin deposition and synovitis.

RESULTS

Following experimental HA induction, Cx3cr1 mRNA expression increased significantly peaking at day 2, accompanied by marked CX3CR1+ macrophage recruitment to synovial tissue. Notably, genetic deletion of Cx3cr1 in F8em1-/- mice did not alter experimental HA development. Joint swelling, hemosiderin deposition, and synovitis were comparable between F8em1-/- and F8em1-/-Cx3cr1-/- mice. Similarly, treatment with a CX3CR1 antagonist did not attenuate the development of HA.

CONCLUSION

Despite marked CX3CR1+ macrophage recruitment during experimental HA, the CX3CL1-CX3CR1 axis is dispensable for the pathogenesis of acute hemophilic synovitis in this mouse model of severe hemophilia A.