Neutrophil-dependent interferonopathy contributes to joint damage in hemophilia.

Patients with severe hemophilia A suffer from recurrent bleeding in synovial joints, which leads to development of hemophilic arthropathy, a progressive condition characterized by permanent joint damage, chronic pain and poor quality of life. Current treatment with factor VIII replacement or factor VIII mimetic therapy provides only partial protection from joint bleeding. Unfortunately, targeted therapies to prevent the development of hemophilic arthropathy remain an unmet clinical need, and the etiological mechanism underlying joint damage in hemophilia is still poorly understood. Using the experimental model of hemophilic arthropathy in Factor 8 total knockout (F8TKO) mice and blood samples from hemophilia A patients with or without active joint bleeding, we show that acute joint bleeding promotes an inflammatory milieu in hemophilia, which triggers the type-I interferon response and downstream signaling in neutrophils, leading to systemic shedding of neutrophil extracellular traps (NETs). Remarkably, therapeutic inhibition of type-I interferon receptor attenuates shedding of NETs and reduces the severity of joint damage in F8TKO mice. The current study is the first to identify a role for NETs in the pathogenesis of hemophilic arthropathy and demonstrates the therapeutic potential of targeting neutrophil-dependent type-I interferon signaling to attenuate the progression of joint damage in hemophilia.