Protective role of systemic furin in immune response–induced arthritis

Abstract

Objective. Rheumatoid arthritis (RA) is an autoimmune joint disease associated with chronic inflammation of the synovium that causes profound damage of joints. Inflammation results in part from the influx of immune cells secreting inflammatory cytokines and the reduction in the number of Treg cells. We undertook this study to assess the effect of furin, a proteinase implicated in the proteolytic activity of various precursor proteins and involved in the regulation of both proteinase maturation and immune cells, in an experimental model of RA.Methods. The effect of furin and its inhibitor ␣1-PDX was tested in mice with collagen-induced arthritis (CIA). Joints were processed for histology and protein expression. Levels of cytokines were measured in joint tissue, and Treg cell numbers were measured in spleens.Results. Furin expression and activity were high in the synovial pannus in RA patients and mice with CIA. Systemic administration of furin prevented increases in the arthritis score, joint destruction, and bone loss, in contrast to systemic administration of the furin inhibitor ␣1-PDX, which enhanced these parameters. By preventing the development of synovial pannus, furin reduced the expression of metalloproteinases in the joints. In contrast, ␣1-PDX enhanced synovial proliferation and the expression and activity of matrix metalloproteinases. Furthermore, furin reversed the local Th1/Th2 balance and restored the number of Treg cells in the spleen, indicating mediation by immune cells.Conclusion. These findings show the protective role of exogenous furin against RA, mediated by an immune response. The data suggest the potential therapeutic use of furin or its derivatives in autoimmune diseases including RA.

The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

“…Furthermore, PCSK inhibitors have relatively recently been suggested as drugs for cancer and infectious diseases (9,10,67). Blocking FURIN also associates with accelerated immune responses, as shown by the spontaneous development of autoimmunity in T cell-specific FURIN cKO mice and by the prevention of experimental arthritis upon recombinant FURIN administration (18,19). Our results here demonstrate that diminished furinA expression reduces mycobacterial loads in a latent infection model, which suggests that PCSK inhibitors could potentially be used to harness also TB.…”

“…The breakage of peripheral immune tolerance in CD4cre-fur fl/fl mice resulted in an age-related progression of a systemic autoimmune disease characterized by excessive numbers of overtly activated CD4 ϩ and CD8 ϩ T cells and an increase in proinflammatory cytokine production. In line with the critical role of FURIN in immune suppression, the administration of exogenous recombinant FURIN can alleviate autoimmunity in an experimental arthritis model (19). Notably, as a germ line Furin gene knockout (KO) in mice is lethal during embryonic development (20), the systemic role of FURIN in immune regulation and infections is still poorly understood.…”

Myeloid cell expressed proprotein convertase FURIN attenuates inflammation

“…In addition, the activation/deactivation of the Caspase-1 cascade, which directly processes IL-1β, plays an important role in the dynamics of macrophage polarization [58]. Previous data also imply a functional connection between PCSK activity and IL-1β; the proteolytic cleavage of the anthrax toxin by FURIN activates Caspase-1 in macrophages [59] and high levels of IL-1β have been observed in an experimental model of arthritis in mice that were treated with a FURIN inhibitor [60]. …”

Proprotein Convertase FURIN Constrains Th2 Differentiation and Is Critical for Host Resistance against Toxoplasma gondii

“…In addition, administering recombinant FURIN can alleviate the over-active immune cells in autoimmune diseases (11). Understanding how FURIN regulates cell-mediated immunity and Th balance is thus critical when such treatments are considered for clinical use.…”

“…Accordingly, PCSK enzymes play a key regulatory role in a multitude of biological events, including development and hormone function (9). Dysregulated proprotein convertase activity also contributes to pathogenic cell behavior, and therefore interfering with PCSK activity is currently being considered as a potential treatment for many diseases including atherosclerosis (10), rheumatoid arthritis (11) and multiple sclerosis (12). …”