Peroxiredoxin-1 is an H2O2 safe-guard antioxidant and signalling enzyme in M1 macrophages

Abstract

Macrophages are characterised by their high plasticity and ability to adapt their phenotype and functionality in response to environmental cues, resulting in a spectrum of activation states the two extremes of which are M1 and M2. Reactive oxygen species, such as hydrogen peroxide, are among the cues that impact macrophage polarisation. Moreover, high levels of hydrogen peroxide play a role in the phagocytic response executed by M1 macrophages. Therefore, macrophages must balance the need to shield themselves from the harmful effects of hydrogen peroxide bursts with the ability to interpret hydrogen peroxide signals from the surroundings and initiate a cellular response. Peroxiredoxins (PRDX) are proteins capable of performing both roles. Specifically, PRDX1 and PRDX5 have been demonstrated to safeguard macrophages against reactive oxygen species while also impacting their polarisation status. Previously conducted studies did not differentiate between the polarisation state of macrophages or investigate the signalling events triggered by PRDXs. In this study, we utilised bone marrow-derived murine macrophages polarised to the M1 and M2 states. Our findings revealed that the expression of PRDX1 was significantly higher in M1 macrophages than in M2 and unpolarised macrophages. Moreover, we present evidence that in M1 macrophages, PRDX1 interacts with ASK1, its established interaction partner, and also binds to other proteins that regulate the cellular antioxidant response. Interestingly, we found that pharmacological elevation of hydrogen peroxide levels leads to an increase in PRDX1 expression on the mRNA level, but not in the highly related PRDX2 expression. Taken together, our findings suggest that PRDX1 plays a critical role in macrophage antioxidant defence and redox signalling, and provide scope for exploring redox-signalling proteins as highly sought-after candidates for macrophage repolarisation.