Recruited monocytes modulate malaria-induced lung injury through CD36-mediated clearance of sequestered infected erythrocytes

Abstract

Pulmonary complications occur in a significant percentage of adults and children during the course of severe malaria. The cellular and molecular innate immune mechanisms that limit the extent of pulmonary inflammation and preserve lung function during severe Plasmodium infections remain unclear. In particular, the contributions to pulmonary complications by parasitized erythrocyte sequestration and subsequent clearance from the lung microvasculature by immune cells have not been clearly defined. We used the Plasmodium berghei ANKA-C57BL/6 mouse model of severe malaria to investigate the mechanisms governing the nature and extent of malaria-associated lung injury. We have demonstrated that sequestration of infected erythrocytes on postcapillary endothelial surfaces results in acute lung injury and the rapid recruitment of CCR2(+)CD11b(+)Ly6C(hi) monocytes from the circulation. These recruited cells remain in the lungs as monocyte-derived macrophages and are instrumental in the phagocytic clearance of adherent Plasmodium berghei-infected erythrocytes. In contrast, alveolar macrophages do not play a significant role in the clearance of malaria-infected cells. Furthermore, the results obtained from Ccr2(-/-), Cd36(-/-), and CD36 bone marrow chimeric mice showed that sequestration in the absence of CD36-mediated phagocytic clearance by monocytes leads to exaggerated lung pathologic features. In summary, our data indicate that the intensity of malaria-induced lung pathologic features is proportional to the steady-state levels of Plasmodium-infected erythrocytes adhering to the pulmonary vasculature. Moreover, the present work has defined a major role of recruited monocytes in clearing infected erythrocytes from the pulmonary interstitium, thus minimizing lung damage.

Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1‐dependent mechanisms of cardiac repair

“…Also in brain, CD36 contributes to phagocytosis during stroke resolution (54), as well as to the neurotoxic activity of infiltrating monocytes in a model of oxygen-glucose deprivation (55); myeloid CD36 has also been linked to hyperlipidemic stroke (56). Recruited monocytes in the lung express CD36 to clear infected erythrocytes in a malaria-injury model, thereby minimizing lung damage (57). In experimental hearts, pretreatment with a selective CD36 ligand agonist, EP 80317, reduced infarct area and increased ejection fraction after ischemia-reperfusion in mice (58).…”

ICAM-1 is a key receptor mediating cytoadherence and pathology in the Plasmodium chabaudi malaria model

“…This is in contrast to the P. berghei ANKA model, where lack of CD36 afforded no protection from cerebral pathology but sequestration was reduced in lungs and adipose tissue [13] and lung pathology, as manifested by vascular leakage, was reduced [14, 45]. However, a recent study of lung pathology in this model used mouse bone-marrow chimeras to show that endothelial damage was greatest when CD36 was expressed on endothelial cells, suggesting that the presence of CD36 on trafficking cells may result in enhanced parasite clearance and hence offer some protection from endothelial damage [14]. This could explain why in this study infection in the complete cd36 − / − mouse KO is no different from that of wild-type mice as the two roles of CD36 could exert a balancing effect.…”

Signaling Strategies of Malaria Parasite for Its Survival, Proliferation, and Infection during Erythrocytic Stage

“…In monocytes, it avails in phagocytosis of iRBC but not concerned with TNF, responsible for sever pathologies (155, 156). During acute lung injury in P. berghei infection, splenic monocytes recruited to the lung tissue cause CD36-mediated phagocytosis of iRBC (157). Future research is expected for unrevealing the prospects of phagocytosis and the involvement of this pathway in activation of adaptive immunity.…”