Regenerating islet-derived 3-gamma regulates pulmonary Th17 immunity by altering the gut microbiome (120.37)

Abstract

Abstract Regenerating islet-derived 3-gamma (Reg3g) is a 17kDa lectin produced by intestinal paneth cells and has bactericidal activity against gram-positive organisms. Here, we find that lung infection with Staphylococcus aureus induces the expression of reg3g and reg3b in a MyD88-dependent manner. Expression of reg3b in the lung was localized to large airway cells, and increased following treatment with IL-17 and IL-22. Further, recombinant Reg3g had strong binding to S. aureus and growth inhibition in vitro. In vivo studies indicated that reg3g-/- mice were capable of clearing S. aureus infection, and produced significantly more IL-17 than control B6 mice. This was associated with increased segmented filamentous bacteria colonization in the gut of Reg3g-/- mice. To test the hypothesis that Reg3g regulates lung Th17 immunity by altering the gut microbiome, mice were treated with antibiotics prior to immunization with ovalbumin plus cholera toxin. Antibiotic treatment reduced lung Th17 numbers in Reg3g-/- mice to the level observed in B6 mice. Finally, gut vaccination with heat-killed Klebsiella pneumoniae increased Th17 cytokine expression in the lung and protected against live challenge, demonstrating the intestinal niche can augment pulmonary immunity. These data demonstrate dual roles for Reg3g in host defense: 1) direct anti-microbial activity against S. aureus, and 2) decreasing SFB levels in the gut, which could negatively impact Th17-mediated host defense.