3.5 Suppression of Complement Activation
Excessive complement activation has been implicated in the pathogenesis of allergic inflammatory disorders such as IgE-independent DAs, and the increased production of the anaphylactic toxins C3a and C5a contributes to the activation of mast cells or basophils, vasodilation and smooth muscle contraction. Either transgenic overexpression of Trx1 in vivo or exogenous injection of Trx1 can reduce choroidal neovascularisation formation in laser-injured mouse models, which is closely related to complement activation of the Trx1 inhibition alternative pathway.52 Complement factor H, a multi-domain and multi-functional protein, functions within the negative feedback that occurs during complement alternative pathway activation. It competes with factor B for C3b binding and accelerates the degradation of C3 convertase into its component.97Trx1 inhibits C3 cleavage into C3a and C3b in a dose-dependent manner and prevents the deposition of C3b, and it inhibits the activation of C3b and reduces the generation of C3 convertase by binding to complement factor H; thus, it enhances the inhibition of C3 cleavage by complement factor H.52
Moreover, Trx1 inhibits the activation of C5 convertase through its active site, thereby preventing the production of C5a and the formation of membrane attack complex53 (Figure 3). The deposition of C5b and C9 is also inhibited by Trx1 in a concentration-dependent manner in all three pathways during their early stages; however, Trx1 does not inhibit the deposition of non-allergic toxin C3b, which has a conditioning effect on bacteria and promotes phagocytosis of phagocytes.98 C5a has strong chemotactic activity in neutrophils and stimulates them to produce a large amount of oxygen free radicals, prostaglandins and arachidonic acid. When Trx1 is injected intravenously into mice, complement-mediated neutrophil recruitment is significantly inhibited in the animals.52,53 Therefore, blockage of complement activation by Trx1 may represent a therapeutic target for relieving IgE-independent allergic inflammation.