title: Endothelial nitric oxide synthase limits the inflammatory response in mouse cutaneous leishmaniasis.
abstract: Endothelial nitric oxide synthase (eNOS) was originally discovered in the cardiovascular system, where it contributes to the regulation of blood pressure and the inhibition of platelet adhesion. Considering that the vascular endothelium is critical for the initiation of inflammatory processes and that eNOS has been detected in certain types of immune cells, we investigated the function of eNOS in C57BL/6 mice infected with Leishmania major, a protozoan parasite that causes a chronic, but self-healing skin disease. C57BL/6 eNOS(-/-) mice developed more severe (but ultimately resolving) skin lesions with strikingly higher numbers of parasites compared to wildtype controls. In accordance with our finding that naive T lymphocytes and Th1 cells (as well as Th2 cells) did not express eNOS after stimulation and that eNOS was not required for Th1 differentiation in vitro, lymph node T cells from L. major-infected wildtype and eNOS(-/-) mice released comparable amounts of IFN-gamma and proliferated equally well. Immunohistological analyses revealed that the expression of inducible NO synthase in the skin and draining lymph nodes of infected mice was completely preserved in the absence of eNOS. However, the skin lesions of eNOS(-/-) mice were characterized by massive infiltrates of granulocytes, which in vitro similar to inflammatory macrophages failed to express eNOS. From these data, we conclude that during cutaneous leishmaniasis eNOS-derived NO, presumably released by vascular endothelial cells, counteracts the recruitment of granulocytes, which are known to function as host cells and trojan horses for Leishmania parasites, and thereby limits the severity of the skin lesions.
authors.affiliation: Microbiology Institute-Clinical Microbiology, Immunology and Hygiene, University Hospital of Erlangen and Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fritzsche
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schleicher
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018450:Disease Progression; D006098:Granulocytes / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology* / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012867:Skin / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D007371:Interferon-gamma; D052250:Nitric Oxide Synthase Type III