The mammalian intestine is colonized by trillions of bacteria that perform essential metabolic functions for their hosts. The mutualistic nature of this relationship depends on maintaining spatial segregation between these bacteria and the intestinal epithelial surface. This segregation is achieved in part by the presence of a dense mucus layer at the epithelial surface and by the production of antimicrobial proteins that are secreted by epithelial cells into the mucus layer. Here, we show that resistin-like molecule β (RELMβ) is a bactericidal protein that limits contact between Gram-negative bacteria and the colonic epithelial surface. Mouse and human RELMβ selectively killed Gram-negative bacteria by forming size-selective pores that permeabilized bacterial membranes. In mice lacking RELMβ, Proteobacteria were present in the inner mucus layer and invaded mucosal tissues. Another RELM family member, human resistin, was also bactericidal, suggesting that bactericidal activity is a conserved function of the RELM family. Our findings thus identify the RELM family as a unique family of bactericidal proteins and show that RELMβ promotes host-bacterial mutualism by regulating the spatial segregation between the microbiota and the intestinal epithelium.antibacterial protein | microbiota | innate immunity | intestinal epithelium
Highlights d Skin microbiota induces epidermal RELMa, which kills bacteria via membrane disruption d RELMa-deficient mice have altered skin microbiota and are more susceptible to infection d Dietary vitamin A is required for RELMa expression d RELMa is required for vitamin-A-dependent resistance to skin infection
Vitamin A is a dietary component that is essential for the development of intestinal immunity. Vitamin A is absorbed and converted to its bioactive derivatives retinol and retinoic acid by the intestinal epithelium, yet little is known about how epithelial cells regulate vitamin A-dependent intestinal immunity. Here we show that epithelial cell expression of the transcription factor retinoic acid receptor β (RARβ) is essential for vitamin A-dependent intestinal immunity. Epithelial RARβ activated vitamin A-dependent expression of serum amyloid A (SAA) proteins by binding directly to Saa promoters. In accordance with the known role of SAAs in regulating Th17 cell effector function, epithelial RARβ promoted IL-17 production by intestinal Th17 cells. More broadly, epithelial RARβ was required for the development of key vitamin A-dependent adaptive immune responses, including CD4+ T-cell homing to the intestine and the development of IgA-producing intestinal B cells. Our findings provide insight into how the intestinal epithelium senses dietary vitamin A status to regulate adaptive immunity, and highlight the role of epithelial cells in regulating intestinal immunity in response to diet.
Vitamin A is a dietary component that is essential for the development of intestinal immunity.Vitamin A is absorbed and converted to its bioactive derivatives retinol and retinoic acid by the intestinal epithelium, yet little is known about how epithelial cells regulate vitamin A-dependent intestinal immunity. Here we show that epithelial cell expression of the transcription factor retinoic acid receptor b (RARb) is essential for vitamin A-dependent intestinal immunity. Epithelial RARb activated vitamin A-dependent expression of serum amyloid A (SAA) proteins by binding directly to Saa promoters. In accordance with the known role of SAAs in regulating Th17 cell effector function, epithelial RARb promoted IL-17 production by intestinal Th17 cells. More broadly, epithelial RARb was required for the development of key vitamin A-dependent adaptive immune responses, including CD4 + T cell homing to the intestine and the development of immunoglobulin A-producing intestinal B cells. Our findings provide insight into how the intestinal epithelium senses dietary vitamin A status to regulate adaptive immunity and highlight the role of epithelial cells in regulating intestinal immunity in response to diet.3 Significance StatementVitamin A is a nutrient that is essential for the development of intestinal immunity. It is absorbed by gut epithelial cells which convert it to retinol and retinoic acid. Here we show that the transcription factor retinoic acid receptor b (RARb) allows epithelial cells to sense vitamin A in the diet and regulate vitamin A-dependent immunity in the intestine. We find that epithelial RARb regulates several intestinal immune responses, including production of the immunomodulatory protein serum amyloid A, T cell homing to the intestine, and B cell production of immunoglobulin A. Our findings provide new insight into how epithelial cells sense vitamin A to regulate intestinal immunity and highlight why vitamin A is so important for immunity to infection. 4The mammalian intestinal epithelium is a vital interface between the external environment and internal tissues. Epithelial cells interact with the environment of the gut lumen by absorbing dietary compounds and by associating with the resident bacterial communities that promote digestion. The intestinal epithelium also orchestrates development of the underlying immune system through the secretion of immunoregulatory proteins (1). Thus, epithelial cells are ideally positioned to capture information about the diet and the microbiota in order to regulate adaptive immunity. While it is known that gut epithelial cells detect intestinal microorganisms through various pathways involving pattern recognition receptors (1), little is known about how epithelial cells sense dietary components to regulate adaptive immunity.Vitamin A is a fat-soluble nutrient that is essential for the development of adaptive immunity to intestinal microorganisms. It is required for immunoglobulin A (IgA) production by intestinal B cells (2), T cell homing to the intestine (3), and t...
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