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.