IFN-γ mediates Experimental Cerebral Malaria by signalling within both the hematopoietic and non- hematopoietic compartments.

5 years ago

IFN-γ mediates Experimental Cerebral Malaria by signalling within both the hematopoietic and non- hematopoietic compartments.

Forman R, Rajkovic I, Couper KN, Tosevski V, Shaw TN, Strangward P, Muller W, Villegas-Mendez A

Experimental cerebral malaria (ECM) is an IFN-γ dependent syndrome. However, whether IFN-γ promotes ECM through direct and synergistic targeting of multiple cell populations or whether it causes ECM through acting primarily on a specific responsive cell type, is currently unknown. Here, using a panel of cell and compartment-specific IFN- γR2 deficient mice, we show that IFN-γ causes ECM by signalling within both the hematopoietic and non-haematopoietic compartments. Mechanistically, hematopoietic and non-haematopoietic compartment-specific IFN-γR signalling exerts additive effects in orchestrating intracerebral inflammation leading to ECM development. Surprisingly, mice with specific deletion of IFN-γR2 expression on myeloid cells, T cells or neurons were completely susceptible to terminal ECM. Utilising a reductionist in vitro system we show that synergistic IFN-γ and TNF stimulation promotes strong activation of brain blood vessel endothelial cells. Combined, our data shows that within the haematopoietic compartment, IFN-γ causes ECM by acting redundantly, or by targeting non-T cell or non-myeloid cell populations. Within the non-haematopoietic compartment, brain endothelial cells, but not neurons, may be the major target of IFN-γ leading to ECM development. Collectively, our data provide information on how IFN-γ mediates development of cerebral pathology during malaria infection.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28874445

DOI: PubMed:28874445