3.1 Eliminating Reactive Oxygen Species and Maintaining Redox Balance
Trx1 can directly remove ROS produced in inflamed tissues and help maintain redox balance.30 Mitsui et al. showed that Trx1 transgenic mice had strong resistance to oxidative stress and a longer life span compared with wild-type (WT) animals.54 Compared with the Trx1 system, the intracellular redox system has similar anti-oxidant mechanisms, such as the glutathione and peroxidase systems, which defend against oxidative stress. The Trx1 and glutathione systems act as backup systems to provide electrons for each other, i.e. the two systems protect cells from oxidative damage synergistically.55,56 In addition, Trx1 is required to provide electrons when peroxidase is used to reduce ROS in organisms.57 Thus, Trx1 plays a key role in the balance of multiple redox systems in the body, and it coordinates the normal operation and function of these systems.
In the allergic state, expression of Trx1 can be induced to reduce the damage caused by excessive ROS. Simultaneously, the Trx1 system restores and refolds oxidised and damaged proteins. Consequently, Trx1 likely plays an important protective role against allergic inflammation.
3.2 Inhibition of MIF
Human MIF, a member of the Trx1 family of proteins that displays thiol reductase activity, was first cloned from T cells in 1989.58 It has inhibitory properties on the migration of macrophages and plays an essential role in cellular immunity, especially in delayed-type hypersensitivity.59 MIF is largely regarded as a pleiotropic inflammatory medium with a wide range of immunoregulatory and pro-inflammatory activities, including the induction of inflammatory cytokines, regulation of macrophage and lymphocyte proliferation and functions similar to those of chemokines.59,60 Furthermore, MIF is directly involved in eosinophil differentiation, survival, activation and migration.18
MIF shares the redox-active motif -Cys-Xxx-Xxx-Cys- with Trx1.61 It has sulfhydryl reductase activity and direct redox reactions with Trx1.62 Several preclinical studies using animal models have found that Trx has beneficial protective functions against various inflammatory diseases. For example, the serum MIF level of Trx1 transgenic mice was significantly lower than that of WT mice in a dextran sodium sulphate-induced colitis mouse model.63 In mice with systemic inflammatory reactions caused by smoking, MIF gene expression in the spleens of Trx1 transgenic mice was inhibited compared with the expression levels in control mice.64 Using a mouse model of asthma, Torii et al. found that MIF production in the lungs of Trx1 transgenic mice was significantly reduced despite similar systemic Th2 responses and IgE concentrations, indicating that Trx1 can suppress airway inflammation by directly inhibiting MIF independent of systemic Th1/Th2 immune modulation.24
In vitro studies have provided direct evidence for the strong anti-MIF effect of Trx1. For instance, the production of MIF in macrophages cultured with LPS and IFN-γ was significantly inhibited by Trx1.63 MIF expression is also suppressed in Trx1-transfected cells,65 and topically applied exogenous Trx1 suppresses the expression of MIF in ICD skin tissues.33 Additionally, MIF can enter cells to induce a series of inflammatory reactions, and cell surface Trx1 is one of the target proteins for MIF internalisation. Specifically, membrane-located Trx1, on the cell surface, binds extracellular MIF with high affinity and blocks MIF internalisation. Exogenous and intracellular Trx1 can also directly bind to MIF, thereby forming a complex that blocks the MIF-induced inflammatory response.66