Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism

J Biol Chem. 2016 Sep 9;291(37):19517-31. doi: 10.1074/jbc.M116.746594. Epub 2016 Jul 29.

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, CD11b(+) cells that expressed selected anti-inflammatory markers accumulated, and expression of inflammatory mediators IFN-γ and TNF-α was reduced. Finally, the M2 macrophage chemokine CCL17 was identified as an essential factor for enhanced survival in the absence of CB2, because CCL17 × Cnr2 double-deficient mice were fully susceptible to ECM. Thus, targeting CB2 may be promising for the development of alternative treatment regimes of ECM.

Keywords: chemokine; endocannabinoid; macrophage; malaria; neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / genetics
  • Arginase / immunology
  • Blood-Brain Barrier / immunology*
  • Blood-Brain Barrier / parasitology
  • Blood-Brain Barrier / pathology
  • Chemokine CCL17 / genetics
  • Chemokine CCL17 / immunology*
  • Disease Models, Animal
  • Disease Susceptibility
  • Female
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology
  • Macrophages / immunology
  • Macrophages / pathology
  • Malaria, Cerebral / genetics
  • Malaria, Cerebral / immunology*
  • Malaria, Cerebral / pathology
  • Male
  • Mannose-Binding Lectins / genetics
  • Mannose-Binding Lectins / immunology
  • Mice
  • Mice, Knockout
  • Neutrophils / immunology
  • Neutrophils / pathology
  • Plasmodium berghei / immunology*
  • Receptor, Cannabinoid, CB2 / genetics
  • Receptor, Cannabinoid, CB2 / immunology*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology

Substances

  • Ccl17 protein, mouse
  • Chemokine CCL17
  • Cnr2 protein, mouse
  • IL10 protein, mouse
  • Lectins, C-Type
  • Mannose-Binding Lectins
  • Receptor, Cannabinoid, CB2
  • Receptors, Cell Surface
  • mannose receptor
  • Interleukin-10
  • Arg1 protein, mouse
  • Arginase