Targeted inhibition of FcRn reduces NET formation to ameliorate experimental ulcerative colitis by accelerating ANCA clearance.

Dysregulated immune responses have now been recognized as an essential stimulator of ulcerative colitis (UC). Neutrophil extracellular traps (NET) were reported as the potential factor in sustaining mucosal inflammation in UC. NET formation further induces antineutrophil cytoplasm autoantibodies (ANCA) that serve as a biomarker in determining the severity of UC, which have a long half-life due to neonatal Fc receptor (FcRn)-mediated recycling. This study aimed to explore the role of the ANCA-NET cycle in UC and evaluate the potential of targeting FcRn in UC treatment. Dextran sodium sulfate-induced mice and rat models were used in this study. anti-rat FcRn monoclonal antibodies were used to block FcRn function in vivo. Disease activity index (DAI) and histopathological score (HS) were estimated to characterize the inflammation severity of UC. Serum concentrations of IgG, ANCA, TNF-α, IL-1β and CRP were measured using specific ELISA kits. Colonic NET-associated protein (NAP) expression was determined by western blotting. Serum ANCA and colonic NAPs showed a positive correlation that varied with changes in serum inflammation-related indexes (IRI; including TNF-α, IL-1β, and CRP) and DAI and HS in mice with UC. Blockade of FcRn significantly reduced serum ANCA levels and colonic NAP expression and effectively decreased serum IRIs, DAI, and HS in rats with UC. Especially during the inflammation recurrence period, blockade of FcRn exerted even better therapeutic effects in rats with UC than salazosulfapyridine. Our results show that anti-FcRn therapy has benefits in UC treatment through reduced colonic NET formation by accelerating serum ANCA clearance.