THE ROLE OF RIPK1 IN PREVENTING MALARIA-INDUCED NEUROINFLAMMATION

Malaria is a hemolytic disease responsible for high morbidity and mortality rates, particularly in Sub-Saharan Africa. Among the complications, severe malarial anemia (SMA) is a threatening condition. Our data showed that SMA induces brain damage by causing neuroinflammation and iron (Fe) accumulation, presumably due to the release of heme into circulation, which is triggered by parasite replication. In agreement, the exogenous administration of heme in mice was shown to enhance the permeability of the blood brain barrier, fostering neuroinflammation. This effect was also observed upon malaria, regardless of parasites’ ability to trigger cerebral or severe forms of malaria. Given that necroptosis underlies the severity of malaria-induced tissue damage, we assessed whether the neuroinflammation, developed during SMA and caused by heme cytotoxicity, is regulated by RIPK1. By using knock-in mice with an inactivate kinase activity, Ripk1S25D, our data demonstrated that those animals were more resistant to the pro-inflammatory priming to the brain caused by the infection, in relation to wild-type controls. The pronounced activation of the immune response in Ripk1S25D infected mice contrasted with the absence of neuroinflammation, as assessed by the significant reduction of brain infiltrated lymphocytes. Similar data were also obtained when injecting these animals with heme, used to mimic the damage induced by hemolytic infections, like malaria. A reduced brain Fe accumulation was found in both infected and heme-injected Ripk1S25D mice, when compared to controls. Overall, our data indicate that the inhibition of necroptosis could become a new therapeutic approach to prevent SMA from causing brain complications.