Fc Alpha Receptor I Co-Stimulation Promotes Inflammatory Responses by Human CD103+ Mucosal Dendritic Cells

Maintaining a proper balance between inflammation and tolerance is essential in the gastrointestinal tract due to the high concentrations of residing bacteria. Disturbance of this delicate balance can lead to over-activation of immune responses as observed in inflammatory bowel disease (IBD). Crucial for regulation of intestinal tolerance are CD103+ dendritic cells (DC), which reside in the lamina propria of the gut. However, upon infection of the lamina propria the local tolerogenic response should be converted into a pro-inflammatory response. Yet, whether and how this requires alterations in CD103+ DCs or activation of other cells, is still largely unknown. Here we have identified a specific combination of stimuli that promotes inflammatory responses by CD103+ DCs. Bacteria that enter the lamina propria are rapidly opsonized by IgA, which subsequently bind to and activate Fc alpha receptor I (FcαRI) on CD103+ DCs. While stimulation of FcαRI alone did not affect monocyte-derived CD103+ DC responses, FcαRI stimulation synergized with Toll-like receptors for the selective production of pro-inflammatory cytokines TNFα, IL-1β, IL-6 and IL-23. Strikingly, FcαRI-induced cytokine production was completely independent of gene transcription, but instead was mediated by modulation of gene translation. Taken together, we have identified a specific combination of stimuli that promotes pro-inflammatory cytokine production by CD103+ DCs, which involves the antibody IgA and its main receptor FcαRI. Our identification of the molecular mechanism behind this process could be important in the pathogenesis of IBD and may provide potential new targets for treatment of this disease.