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

Alferink, Judith; Specht, Sabine; Arends, Hannah; Schumak, Beatrix; Schmidt, Kim; Ruland, Christina; Lundt, Ramona; Kemter, Andrea; Dlugos, Andrea; Kuepper, Janina M; Poppensieker, Karola; Findeiss, Matthias; Albayram, Önder; Otte, David-M; Marazzi, Janine; Gertsch, Jürg; Förster, Irmgard; Maier, Wolfgang; Scheu, Stefanie; Hoerauf, Achim; ... (2016). Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism. Journal of biological chemistry, 291(37), pp. 19517-19531. American Society for Biochemistry and Molecular Biology 10.1074/jbc.M116.746594

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Marazzi, Janine and Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0021-9258

Publisher:

American Society for Biochemistry and Molecular Biology

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

19 Apr 2017 14:40

Last Modified:

19 Apr 2017 14:40

Publisher DOI:

10.1074/jbc.M116.746594

PubMed ID:

27474745

Uncontrolled Keywords:

chemokine; endocannabinoid; macrophage; malaria; neuroinflammation

BORIS DOI:

10.7892/boris.94102

URI:

https://boris.unibe.ch/id/eprint/94102

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