Role of NINJ1 in Gout Flare and Potential as a Drug Target

Abstract

To determine the role of nerve injury-induced protein 1 (NINJ1) introduced plasma membrane rupture (PMR) and damage-associated molecular patterns (DAMPs) release in the pathogenesis and progression of gout and to explore the potential of NINJ1 as a therapeutic target in gout. Methods: Both peripheral blood mononuclear cells (PBMCs) and serum sample from gout patients (n = 58) and healthy controls (n = 16) were collected and processed to NINJ1 expression, lactate dehydrogenase (LDH) detection, NINJ1 inhibition, and NINJ1 expression experiments, respectively. NINJ1 knockdown was carried out by lentivirus in a monosodium urate (MSU) induced rat model, and NINJ1 neutralizing antibody was applied in a MSU induced mouse model. Results: Our results found that NINJ1 was upregulated during a gout flare, and the resulting induction of PMR correlated with gout progression. NINJ1 knockdown significantly reduced the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and joint swelling in the rat model, and NINJ1 neutralizing antibody also significantly reduced gout flare in the mouse model and PBMCs. Moreover, NINJ1 expression is under NLRP3 inflammasome produced interleukin (IL)-1β control. Conclusion: These results support the notion of a pathogenic role of NINJ1 introduced PMR in gout and provide a detailed mechanism for gout pathogenesis involving inflammatory cell death and DAMPs release introduced by IL-1β. In addition, targeting NINJ1 might be a potential therapeutic approach for gout.

Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury

“…These results establish anti-mouse NINJ1 antibody clone D1 as a potent inhibitor of PMR associated with apoptosis or pyroptosis. A commercial anti-NINJ1 antibody (BD Bioscience clone 50) and a NINJ1 26–37 peptide have been used to block mouse NINJ1 in vivo 9 – 11 , but neither reagent blocked nigericin-induced PMR in BMDMs (Extended Data Fig. 2a–c ).…”