IgG Fc receptors (FcγRs) play a role in activating the immune system and in maintaining peripheral tolerance, but their role in atherosclerosis is unknown. We generated double-knockout (DKO) mice by crossing apolipoprotein E–deficient mice (apoE ^−/− ) with FcγR γ chain–deficient mice (γ ^−/− ). The size of atherosclerotic lesions along the aorta was approximately 50% lower in DKO compared with apoE ^−/− control mice, without differences in serum lipid levels. The macrophage and T-cell content of lesions in the DKO were reduced by 49±6% and 56±8%, respectively, compared with the content in apoE ^−/− lesions. Furthermore, the expression of monocyte chemoattractant protein-1 (MCP-1), RANTES ( R egulated on A ctivated N ormal T -cell E xpressed and S ecreted), and intercellular adhesion molecule-1 (ICAM-1) and the activation of nuclear factor-κB (NF-κB) were significantly reduced in aortic lesions from DKO mice. In vitro, vascular smooth muscle cells (VSMCs) from both γ ^−/− and DKO mice failed to respond to immune complexes, as shown by impaired chemokine expression and NF-κB activation. ApoE ^−/− mice have higher levels of activating FcγRI and FcγRIIIA, and inhibitory FcγRIIB, compared with wild-type mice. The DKO mice express only the inhibitory FcγRIIB receptor. We conclude that FcγR deficiency limits development and progression of atherosclerosis. In addition to leukocytes, FcγR activation in VSMCs contributes to the inflammatory process, in part, by regulating chemokine expression and leukocyte invasion of the vessel wall. These results underscore the critical role of FcγRs in atherogenesis and support the use of immunotherapy in the treatment of this disease.

There is significant evidence that brain-infiltrating CD8⁺ T cells play a central role in the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the mechanisms through which they mediate their pathogenic activity during malaria infection remain poorly understood. Utilizing intravital two-photon microscopy combined with detailed ex vivo flow cytometric analysis, we show that brain-infiltrating T cells accumulate within the perivascular spaces of brains of mice infected with both ECM-inducing (P. berghei ANKA) and non-inducing (P. berghei NK65) infections. However, perivascular T cells displayed an arrested behavior specifically during P. berghei ANKA infection, despite the brain-accumulating CD8⁺ T cells exhibiting comparable activation phenotypes during both infections. We observed T cells forming long-term cognate interactions with CX₃CR1-bearing antigen presenting cells within the brains during P. berghei ANKA infection, but abrogation of this interaction by targeted depletion of the APC cells failed to prevent ECM development. Pathogenic CD8⁺ T cells were found to colocalize with rare apoptotic cells expressing CD31, a marker of endothelial cells, within the brain during ECM. However, cellular apoptosis was a rare event and did not result in loss of cerebral vasculature or correspond with the extensive disruption to its integrity observed during ECM. In summary, our data show that the arrest of T cells in the perivascular compartments of the brain is a unique signature of ECM-inducing malaria infection and implies an important role for this event in the development of the ECM-syndrome. Cerebral malaria is the most severe complication of Plasmodium falciparum infection. Utilizing the murine experimental model of cerebral malaria (ECM), it has been found that CD8⁺ T cells are a key immune cell type responsible for development of cerebral pathology during malaria infection. To identify how CD8⁺ T cells cause cerebral pathology during malaria infection, in this study we have performed detailed in vivo analysis (two photon imaging) of CD8⁺ T cells within the brains of mice infected with strains of malaria parasites that cause or do not cause ECM. We found that CD8⁺ T cells appear to accumulate in similar numbers and in comparable locations within the brains of mice infected with parasites that do or do not cause ECM. Importantly, however, brain accumulating CD8⁺ T cells displayed significantly different movement characteristics during the different infections. CD8⁺ T cells interacted with myeloid cells within the brain during infection with parasites causing ECM, but this association was not required for development of cerebral complications. Furthermore, our results suggest that CD8⁺ T cells do not cause ECM through the widespread killing of brain microvessel cells. The results in this study significantly improve our understanding of the ways through which CD8⁺ T cells can mediate cerebral pathology during malaria infection.

Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum–infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter–endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin–induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC–induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised.