title: VEGF and LPS synergistically silence inflammatory response to Plasmodium berghei infection and protect against cerebral malaria.
abstract: Malaria infection induces, alongside endothelial damage and obstruction hypoxia, a potent inflammatory response similar to that observed in other systemic diseases caused by bacteria and viruses. Accordingly, it is increasingly recognised that cerebral malaria (CM), the most severe and life threatening complication of Plasmodium falciparum infection, bears a number of similarities with sepsis, an often fatal condition associated with a misregulated inflammatory response triggered by systemic microbial infections. Using a Plasmodium berghei ANKA mouse model, histology, immunohistochemistry and gene expression analysis, we showed that lipopolysaccharide S (LPS), at doses that normally induce inflammation tolerance, protects P. berghei infected mice against experimental CM (ECM). Vascular endothelial growth factor (VEGF) preserved blood vessel integrity, and the combination with LPS resulted in a strong synergistic effect. Treated mice did not develop ECM, showed a prolonged survival and failed to develop a significant inflammatory response and splenomegaly in spite of normal parasite loads. The protective role of VEGF was further confirmed by the observation that the treatment of P. berghei infected C57BL/6 and Balb/c mice with the VEGF receptor inhibitor axitinib exacerbates cerebral pathology and aggravates the course of infection. Infected mice treated with VEGF and LPS showed an induction of the anti-inflammatory genes Nrf2 and HO-1 and a suppression to basal levels of the genes IFN-γ and TNF-α. These results provide the rationale for developing new therapeutic approaches against CM and shed new light on how the inflammatory process can be modulated in the presence of systemic infectious diseases.
authors.forename: Miriam
authors.initials: M
authors.lastname: Canavese
authors.forename: Tania
authors.initials: T
authors.lastname: Dottorini
authors.forename: Andrea
authors.initials: A
authors.lastname: Crisanti
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D000077784:Axitinib; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004357:Drug Synergism; D007093:Imidazoles / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects*; D007191:Indazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000276:immunology / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000517:prevention & control; D010962:Plasmodium berghei / Q000302:isolation & purification*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D000077784:Axitinib; D002352:Carrier Proteins; D007093:Imidazoles; D007191:Indazoles; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000099231:Lipopolysaccharide-Binding Protein; C467480:vascular endothelial growth factor A, mouse
keywords: Angiogenesis,; Cerebral malaria,; Cytokines; Inflammation,; Vascular endothelial growth factor,