Circadian Control of the Response of Macrophages to Plasmodium spp.-Infected Red Blood Cells.

In this study, we sought to determine whether the intensity of the immune response to Plasmodium spp., the parasite causing malaria, depends on time of infection. For this, we considered the known existence of a circadian clock in immune cells which regulates several aspects of the immune response. Experiments were performed using mouse bone marrow-derived macrophages (BMDMs) stimulated ex vivo with red blood cells infected with Plasmodium berghei ANKA (iRBCs) or uninfected RBCs. First, we identified that lysed iRBCs triggered an immune response in macrophages. Then, by stimulating at 4 different circadian time points (16 h, 22 h, 28 h or 34 h post-synchronization of the cells clock), rhythms in reactive oxygen species and cytokines/chemokines were found. Furthermore, the analysis of the macrophage proteome and phosphoproteome revealed global changes according to treatment (iRBC or RBC) and to the circadian time point. In summary, our findings showed that the circadian clock within macrophages determines the magnitude of immune response upon stimulation with iRBCs, along with changes of the cell proteome and phosphoproteome.