Leishmania amazonensis infection impairs dendritic cell migration from the inflammatory site to the draining lymph node

BACKGROUND: In vitro studies show that Leishmania infection decreases the adhesion of inflammatory phagocytes to connective tissue by a mechanism dependent on the modulation of integrin function. However, we know little about the influence of this reduction in leukocyte adhesion on parasite dissemination from the infection site. METHODS: In this work, we used a model of chronic peritonitis induced by thioglycollate to study the effect of L. amazonensis infection on the ability of inflammatory phagocyte populations to migrate from an inflammatory site to the draining lymph node. Uninfected or Leishmania-infected thioglycollate-elicited peritoneal exudate cells were transferred from C57BL/6 to BALB/c mice or from Ly5.1+ to Ly5.1- mice. The transferred cells were injected into the peritoneal cavity and tracked to the draining lymph node. RESULTS: Migrating cells corresponded to approximately 1% of the injected leukocytes. The proportion of migrating CD11b+CD11c+ (myeloid dendritic cell) was lower after incubation with Leishmania (1.3 to 2.6 times lower in the experiments using C57BL/6 to BALB/c animals and 2.7 to 3.4 times lower in the experiments using Ly5.1+ to Ly5.1- animals) than after leukocyte incubation with medium alone (P < 0.01). There was no consistent decrease in the migration of CD11b+F4/80+ (macrophage) or SSChi GR-1+ (neutrophil) populations. CONCLUSIONS: Coincubation with Leishmania changes the migratory pattern of dendritic cells in vivo. Such changes in dendritic cell migration may be associated with immunological events that maintain inflammation at the sites of infection

Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders

There is a long-standing paradox that N-methyl-D-aspartate receptors (NMDARs) can both promote neuronal health and kill neurons. Recent studies show that NMDAR-induced responses depend on the receptor location: stimulation of synaptic NMDARs, acting primarily through nuclear Ca(2+) signaling, leads to the build-up of a neuroprotective ‘shield’, whereas stimulation of extrasynaptic NMDARs promotes cell death. These differences result from the activation of distinct genomic programmes and opposing actions on intracellular signalling pathways. Perturbations in the balance between synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in acute ischaemia and Huntington’s disease and could be a common theme in the aetiology of neurodegenerative diseases. Neuroprotective therapies should aim to both enhance the effect of synaptic activity and disrupt extrasynaptic NMDAR-dependent death signalling