Constitutive, intestinal IgA secretion is regulated by NLRP3-derived IL-1 and confers protection from enterotoxin-induced fluid accumulation

A role for interleukin (IL)-17 in the regulation of polymeric immunoglobulin receptor (pIgR) expression at mucosal surfaces has recently been described (Jaffar et al, Cao et al). In this study we investigated whether constitutive IL-17 production in the gastrointestinal tract (GIT) was dependent on NLRP3 inflammasome-derived IL-1β and analysed the consequences of deficiency in components of this pathway on homeostatic secretory antibody responses.  We found that both NLRP3^-/- and IL-1R^-/- mice had significant impairments in their ability to produce and secrete IgA in the GIT and lungs under steady-state conditions. Moreover, intestinal exposure to cholera toxin (CT) triggered rapid secretion of IgA into the lumen in an IL-17, IL-1 and NLRP3-dependent manner. We hypothesised that this secretory IgA might be protective in an enteric insult setting. Indeed we observed an increased susceptibility to CT-induced enterotoxicity in IL-17R^-/-, IL-1R^-/- and NLRP3^-/- mice correlating with reduced faecal IgA levels in these strains. These findings suggest a key role for the inflammasome-IL-1-IL-17 axis in facilitating optimal humoral immunity at the mucosae and identify a protective role for non-specific, secretory IgA in an enterotoxin challenge model.