Abstract
Immune activation associates with the intracellular generation of reactive oxygen species (ROS). To elicit effective immune responses, ROS levels must be balanced. Emerging evidence shows that ROS-mediated signal transduction can be regulated by selenoproteins such as methionine sulfoxide reductase B1 (MsrB1). However, how the selenoprotein shapes immunity remains poorly understood. Here, we demonstrated that MsrB1 plays a crucial role in the ability of dendritic cells (DCs) to provide the antigen presentation and costimulation that are needed for cluster of differentiation antigen four (CD4) T-cell priming in mice. We found that MsrB1 regulated signal transducer and activator of transcription-6 (STAT6) phosphorylation in DCs. Moreover, both in vitro and in vivo, MsrB1 potentiated the lipopolysaccharide (LPS)-induced Interleukin-12 (IL-12) production by DCs and drove T-helper 1 (Th1) differentiation after immunization. We propose that MsrB1 activates the STAT6 pathway in DCs, thereby inducing the DC maturation and IL-12 production that promotes Th1 differentiation. Additionally, we showed that MsrB1 promoted follicular helper T-cell (Tfh) differentiation when mice were immunized with sheep red blood cells. This study unveils as yet unappreciated roles of the MsrB1 selenoprotein in the innate control of adaptive immunity. Targeting MsrB1 may have therapeutic potential in terms of controlling immune reactions.
Highlights
Reduction–oxidation (Redox) reactions participate in diverse physiological processes
It is possible that one of these reactive oxygen species (ROS)-mediated cellular cross-talk mechanisms involves the methionine reductase methionine sulfoxide reductase B1 (MsrB1): this is supported by two studies that show that MsrB1 in bone marrowderived macrophages counters the oxidizing activity of a molecule interacting with CasL protein (Mical) monooxygenase on two Met residues in actin [16]
bone marrow-derived DCs (BMDCs) (or bone marrow-derived macrophages, which were generated as described above for BMDCs except macrophage colony-stimulating factor (M-CSF) was used) were lysed in protease inhibitor- and phosphatase inhibitor-containing CelLytic M buffer (Sigma, Burlington, MA, USA) and 20 μg of the cell lysates were separated via 15% or 7.5% SDS-PAGE, transferred to a polyvinylidene fluoride (PVDF) membrane, stained with primary antibodies, incubated with horseradish peroxidase (HRP)-labeled Immunoglobulin G (IgG) (Bio-Rad, Hercules, CA, USA), and visualized with enhanced chemiluminescence (ECL) clarity substrate (Bio-Rad, Hercules, CA, USA)
Summary
Reduction–oxidation (Redox) reactions participate in diverse physiological processes One of these Redox reactions is protein oxidation, which is achieved by reactive oxygen species (ROS), and plays an important role in regulating cellular signal transduction, metabolism, and protein turnover and activity [1]. It is possible that one of these ROS-mediated cellular cross-talk mechanisms involves the methionine reductase MsrB1: this is supported by two studies that show that MsrB1 in bone marrowderived macrophages counters the oxidizing activity of a molecule interacting with CasL protein (Mical) monooxygenase on two Met residues in actin [16]. We propose that Met reduction by MsrB1 may control STAT6 phosphorylation, which in turn activates the maturation and T-cell-stimulatory functions of DCs
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