title: iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice.
abstract: Leishmania major parasites reside and multiply in late endosomal compartments of host phagocytic cells. Immune control of Leishmania growth absolutely requires expression of inducible Nitric Oxide Synthase (iNOS/NOS2) and subsequent production of NO. Here, we show that CD11b+ CD11c+ Ly-6C+ MHC-II+ cells are the main iNOS-producing cells in the footpad lesion and in the draining lymph node of Leishmania major-infected C57BL/6 mice. These cells are phenotypically similar to iNOS-producing inflammatory DC (iNOS-DC) observed in the mouse models of Listeria monocytogenes and Brucella melitensis infection. The use of DsRed-expressing parasites demonstrated that these iNOS-producing cells are the major infected population in the lesions and the draining lymph nodes. Analysis of various genetically deficient mouse strains revealed the requirement of CCR2 expression for the recruitment of iNOS-DC in the draining lymph nodes, whereas their activation is strongly dependent on CD40, IL-12, IFN-gamma and MyD88 molecules with a partial contribution of TNF-alpha and TLR9. In contrast, STAT-6 deficiency enhanced iNOS-DC recruitment and activation in susceptible BALB/c mice, demonstrating a key role for IL-4 and IL-13 as negative regulators. Taken together, our results suggest that iNOS-DC represent a major class of Th1-regulated effector cell population and constitute the most frequent infected cell type during chronic Leishmania major infection phase of C57BL/6 resistant mice.
authors: Laboratoire de Parasitologie, Université Libre de Bruxelles, Brussels, Belgium.
authors: Carl
authors: C
authors: De Trez
authors: Stefan
authors: S
authors: Magez
authors: Shizuo
authors: S
authors: Akira
authors: Bernhard
authors: B
authors: Ryffel
authors: Yves
authors: Y
authors: Carlier
authors: Eric
authors: E
authors: Muraille
mesh_terms: D000818:Animals; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology / Q000469:parasitology; D005434:Flow Cytometry; D007249:Inflammation / Q000201:enzymology / Q000469:parasitology; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000378:metabolism; D010641:Phenotype; D054390:Receptors, CCR2 / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: C515335:Ccr2 protein, mouse; D016207:Cytokines; D008164:Luminescent Proteins; D054390:Receptors, CCR2; C413663:fluorescent protein 583; D052247:Nitric Oxide Synthase Type II