Cannabinoid receptor 2 modulates susceptibility to experimental cerebral malaria through a CCL17-dependent Mechanism

Alferink J., Specht S., Arends H., Schumak B., Schmidt K., Ruland C., Lundt R., Kemter A., Dlugos A., Kuepper J., Poppensieker K., Findeiss M., Albayram N., Otte D., Marazzi J., Gertsch J., Förster I., Maier W., Scheu S., Hoerauf A., Zimmer A.

Abstract

Cerebral malaria is a severe and often fatal complication of Plasmodium falciparum infection. It is characterized by parasite sequestration, a breakdown of the blood-brain barrier, and a strong inflammation in the brain. We investigated the role of the cannabinoid receptor 2 (CB2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ECM). Strikingly, mice with a deletion of the CB2-encoding gene (Cnr2 -/- ) inoculated with Plasmodium berghei ANKA erythrocytes exhibited enhanced survival and a diminished blood-brain barrier disruption. Therapeutic application of a specific CB2 antagonist also conferred increased ECM resistance in wild type mice. Hematopoietic derived immune cells were responsible for the enhanced protection in bone marrow (BM) chimeric Cnr2 -/- mice. Mixed BM chimeras further revealed that CB2-expressing cells contributed to ECM development. A heterogeneous CD11b + cell population, containing macrophages and neutrophils, expanded in the Cnr2 -/- spleen after infection and expressed macrophage mannose receptors, arginase-1 activity, and IL-10. Also in the Cnr2-/- brain,