The enzyme inhibitory activity of helminth-derived serine protease inhibitor rapidly establishes immune tolerance to ameliorate allergic diseases

Allergic diseases are a class of important immune imbalance diseases that lack effective cures. Helminth-derived serine protease inhibitors (serpins) exert immunoregulatory effects similar to those of helminth, are controllable, have few side effects, and have great application potential in correcting unbalanced immune responses. However, the immune regulatory effects and mechanisms mediated by the enzyme inhibitory activity of helminth-derived serpins have not been investigated or clarified in previous studies. We obtained mutant serpin proteins with significantly reduced enzyme inhibitory activity by predicting and mutating the single key amino acid. The therapeutic effect of immunoregulation mediated by enzyme inhibitory activity of serpin on allergic inflammation was investigated based on an acute allergy model constructed in OVA-specific T-cell receptor transgenic C57BL/6 mice. Unlike the Trichinella spiralis-derived serpin (Ts-serpin), the mutant proteins showed significantly reduced inhibitory activity against the chymotrypsin and elastase. Meanwhile, the immunosuppressive ability of the mutant proteins was weakened and mutant protein intervention groups showed more severe allergic inflammation in the lungs. Additionally, enzyme inhibitory activity regulates the differentiation of macrophages and Treg cells to establish immune tolerance, which is the key to rapidly improving lung injury at the challenge and treatment stages of allergy. These findings suggest that the rapid regulatory properties of enzymatic reactions have great potential in the prevention and treatment of allergic inflammation.