Alleviation of arthritis through prevention of neutrophil extracellular traps by an orally available inhibitor of protein arginine deiminase 4

Abstract

Protein arginine deiminases (PAD) 4 is an enzyme that catalyzes citrullination of protein and its role in autoimmune diseases has been established through clinical genetics and gene knock out studies in mice. Further, studies with PAD4 – deficient mice have shown that PAD4 deficiency does not lead to increased infection or immune suppression, which makes PAD4 an attractive therapeutic target for auto-immune and inflammatory diseases. PAD4 has critical enzymatic role of promoting chromatin decondensation and neutrophil extracellular traps (NETs) formation that is associated with a number of immune-mediated pathological conditions. Here, we present a non-covalent PAD4 inhibitor JBI-589 with high PAD4 isoform selectivity and delineated its binding mode at 2.88 Å resolution by X-ray crystallography. We confirmed its effectiveness in inhibiting NET formation in vitro. Additionally, by using two mouse arthritis models for human rheumatoid arthritis (RA), the well-known disease associated with PAD4 clinically, we established its efficacy in vivo. These results suggest that JBI-589 would be beneficial for both PAD4 and NET-associated pathological conditions.

Neutrophil attachment via Mac-1 ( α M β 2 ; CD11b/CD18; CR3) integrins induces PAD4 deimination of profilin and histone H3

“…This is in contrast to inflammatory stimuli, which rapidly induce chromatin NET release [24]. PAD4 contribution to NET release has been documented in numerous studies [13] and recently also convincingly tied to thrombosis [52], cancer progression [53] and autoimmune disease [54]. Therefore, it is important to clearly define the relation between histone deimination and NET release.…”

Anti–Peptidylarginine Deiminase 4 Autoantibodies and Disease Duration as Predictors of Treatment Response in Rheumatoid Arthritis

“…This finding suggests that anti‐PAD4 antibodies may be more effective as predictors of treatment response to therapies with mechanisms of action more proximal to PAD4 function or immune recognition. It will, therefore, be important to evaluate the use of anti‐PAD4 antibodies in predicting treatment response to B cell or antibody targeted therapies, as well as to PAD enzyme inhibitors, which are currently being tested in preclinical mouse models of inflammatory arthritis 25–27 . As novel DMARDs with new mechanisms of action reach the clinic, it will be important to revisit the predictive ability of anti‐PAD antibodies in the early RA population to stop the accumulation of future joint damage.…”

Neutrophil extracellular traps in rheumatoid arthritis and periodontitis: Contribution of PADI4 gene polymorphisms

“…Recently, NET inhibition therapy has been investigated for the treatment of several immune‐mediated diseases, including RA (Jiang et al, 2023) and systemic lupus erythematosus (Rysenga et al, 2023). Along these lines, the use of selective PAD4 inhibitors that inhibit the formation of NETs, citrullination of histones and consequently the generation of ACPAs may represent potential therapeutic interventions in the field of autoimmune and inflammatory diseases (Gajendran et al, 2023). Our data indicate that individuals with periodontitis may benefit from NET reduction through PAD4 inhibition.…”