Retinol plays a vital role in the immune response to infection, yet proteins that mediate retinol transport during infection have not been identified. Serum amyloid A (SAA) proteins are strongly induced in the liver by systemic infection and in the intestine by bacterial colonization, but their exact functions remain unclear. Here we show that mouse and human SAAs are retinol binding proteins. Mouse and human SAAs bound retinol with nanomolar affinity, were associated with retinol in vivo, and limited the bacterial burden in tissues after acute infection. We determined the crystal structure of mouse SAA3 at a resolution of 2 Å, finding that it forms a tetramer with a hydrophobic binding pocket that can accommodate retinol. Our results thus identify SAAs as a family of microbe-inducible retinol binding proteins, reveal a unique protein architecture involved in retinol binding, and suggest how retinol is circulated during infection.DOI: http://dx.doi.org/10.7554/eLife.03206.001

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

A case-case-control study was conducted to identify independent risk factors for recovery of Escherichia coli strains producing CTX-M-type extended-spectrum ␤-lactamases (

SAAving vitamin A–mediated immunity The vitamin A metabolite retinol is critical for B and T cell development and homing to the gut. Intestinal myeloid cells such as dendritic cells and macrophages take up retinol and process it into retinoic acid (RA), which in turn initiates RA-dependent gene expression programs in lymphocytes. Bang et al . identified LDL receptor-related protein 1 (LRP1) as a myeloid cell surface receptor for retinol. LRP1 binds retinol chaperoned by serum amyloid A (SAA) proteins, and SAA–retinol complexes are then endocytosed and metabolized by myeloid cells. Mice lacking either Saa or myeloid-specific Lrp1 exhibited profound impairments in vitamin A–mediated immunity. B and T cell trafficking to the intestine, immunoglobulin A production by B cells, and protection from enteric Salmonella Typhimurium infection were all diminished when either of these crucial players was missing. —STS

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...

Current atopic dermatitis (AD) models link epidermal abnormalities in lesional skin to cytokine activation. However, there is evolving evidence of systemic immune activation and detectable abnormalities in non-lesional skin. Since some of the best single correlations with severity (Scoring of AD/SCORAD) are not only detected in lesional, but also in non-lesional skin and blood, more complex biomarker models of AD are needed. We thus performed extensive biomarker measures in these compartments using univariate and multivariate approaches to correlate disease biomarkers with SCORAD and with a combined hyperplasia score (thickness and K16 mRNA) at baseline and after Cyclosporine A/CsA treatment in 25 moderate-to-severe AD patients. Significant increases in serum cytokines and chemokines (IL-13, IL-22, CCL17) characterized AD (vs. healthy) individuals and were reduced with treatment. SCORAD correlated with immune (IL-13, IL-22) and epidermal (thickness, K16) measures in lesional, and even more strongly, in non-lesional AD skin. Similarly, serum cytokines had higher correlations with non-lesional markers. Using multivariate approaches improved the correlations with SCORAD. Overall, the non-lesional skin models showed the strongest correlations, with further improvement upon integration of serum markers. Even higher correlations were observed between tissue biomarkers and the hyperplasia score. These data highlight the emerging systemic nature of AD.

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