Our data suggest that individuals with low erythrocyte CR1 are less equipped to mop up these ICs than individuals with high erythrocyte CR1 and are more likely to develop complications as a result. This is complicated further
by the fact that individuals afflicted by some of these diseases develop low CR1 levels as a result of the infection [16,17,24]. In addition, we have Bortezomib reported that the level of CR1 can vary with age, and young children aged from 6 to 24 months have the lowest levels of CR1 [15,21]. This population is at greatest risk from complications due to Plasmodium falciparum infection [29]. Young children are known to produce more TNF-α during malaria infection than older children, regardless of the level of parasitaemia [30], and differential capacity to remove ICs during malaria infection may be one potential explanation. We have provided evidence for a unique role of red cells in the stimulation of TNF-α production by presenting ICs and cross-linking Fcγ receptors on macrophages. This phenomenon may be important whenever slow circulation allows close contact between erythrocytes and monocyte/macrophages, such as in the liver and the spleen, leading to local production of proinflammatory cytokines. In the setting of P. falciparum malaria,
this could also happen in capillaries of the brain and other tissues where infected erythrocytes tend to adhere to the endothelium and sequester, slowing down the circulation. This is the pathognomonic feature
of cerebral Opaganib malaria, one of the deadliest complications of this infection. In these capillaries, local production of TNF-α has been documented by immunohistochemistry [31]. We propose that presentation of ICs to monocytes/macrophages by red cells is one possible mechanism for the localized production of proinflammatory cytokines in sequestered capillaries. In addition, IC-loaded red cells in microhaemorrhages of patients with CM could stimulate microglial cells, resident macrophages that express Fcγ receptors [32]. Differential expression of CR1 on red cells is an appealing explanation for the increased susceptibility to cerebral malaria of older children compared to young children [16]. However, our Dichloromethane dehalogenase data do not support that differences in CR1 expression level can lead to differences in the ability of red cells to stimulate macrophages. In conclusion, we have demonstrated that erythrocytes can play a dual role in immune regulation, removing ICs from circulation to prevent inflammation and at the same time being capable of stimulating an inflammatory response by presenting ICs to macrophages. Our findings justify further exploration of the role of these mechanisms in the pathology of IC-mediated diseases such as malaria. This work was supported by NIH grant HL71502 (Principle Investigator José A. Stoute). We are grateful to individuals who participated in the study.