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-γ and MyD88 molecules with a partial contribution of TNF-α 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.

Identification of Immune Effectors Essential to the Control of Primary and Secondary Intranasal Infection with Brucella melitensis in Mice

“…The chemokine receptor CCR2 has been implicated in the recruitment of inflammatory monocytes during infection (40). CCR2 deficiency impaired development of a protective immune response in several infectious models (40,59,60). We observed that CCR2 deficiency had no impact on the course of Brucella infection in the lungs, liver, or spleen at all time points tested.…”

IL-4–producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases

“…We observed that parasite replication in the footpad of B-IL-4 −/− and IL-4 −/− chimeras was controlled to a greater degree than in the LN compared with μMT B-WT chimeras. The footpad has a higher frequency of iNOS-secreting macrophages and DCs to host parasites than the LN and is capable of killing intracellular parasites (25,27), which might account for a slower but effective control in the LN. This was further accompanied by strikingly reduced detrimental type 2 antibody (Fig.…”

Les cellules dendritiques inflammatoires

“…Après cette description initiale, de nombreuses études ont montré chez la souris l'existence d'une population cellulaire comparable dans de nombreux cas d'inflammation causée par des pathogènes, qu'il s'agisse de bactéries (Listeria monocytogenes, Streptococcus pneumoniae, Salmonella typhimurium, etc.) [4][5][6], virus (virus de l'herpès, virus de la grippe, etc.) [6][7][8], levures ou parasites [9,10].…”

“…Différents groupes ont ainsi montré que, lors d'une inflammation, des monocytes injectés à des souris se différenciaient en cellules dendritiques inflammatoires [4,6,9,12,19]. L'utilisation de souris déficientes pour le récepteur de chimiokine CCR2, récepteur indispensable à la migration des monocytes, a permis d'aboutir à la même conclusion : l'absence de recrutement des monocytes sur le lieu d'inflammation compromet l'apparition des cellules dendritiques inflammatoires dont le nombre est alors sévèrement diminué [5,8,9,13,20]. Si l'on sait que la formation des cellules dendritiques inflammatoires n'est pas affectée par l'absence du ligand de Flt3 [19], on connaît mal en revanche les molécules impliquées dans la différenciation des monocytes en cellules dendritiques inflammatoires.…”