Serum amyloid A delivers retinol to intestinal myeloid cells to promote adaptive immunity

Description 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 Serum amyloid A promotes gut immunity by delivering retinol to retinoic acid–producing myeloid cells through the endocytic receptor LRP1. INTRODUCTION Vitamin A is a lipid-soluble nutrient that is absorbed from the diet by intestinal epithelial cells and converted to retinol. This product of vitamin A metabolism is essential for intestinal adaptive immunity because it directs the development of B and T cells and promotes their recruitment to the intestine. Consequently, vitamin A deficiency confers increased susceptibility to infectious diseases of the intestine. Intestinal myeloid cells play a central role in the development of vitamin A—dependent intestinal immunity. Certain myeloid cells convert retinol to retinoic acid (RA) and then pass the RA to developing B and T cells. This activates RA-dependent gene expression programs that direct B and T cells to home to the intestine and induces immunoglobulin A (IgA) production by B cells. RATIONALE A major unanswered question is how intestinal myeloid cells acquire retinol for conversion to RA. Retinol is lipophilic, necessitating transport by retinol-binding proteins that shield it from the aqueous environment. However, proteins that deliver retinol to myeloid cells remain unidentified. Serum amyloid A (SAA) proteins are retinol-binding proteins expressed in the intestinal epithelium. Epithelial cell expression of SAAs requires both the intestinal microbiota and dietary vitamin A. SAAs are also produced by the liver and circulate in the serum with bound retinol after systemic bacterial infection. Thus, SAAs are retinol-binding proteins that transport retinol in response to microbial challenge. However, the cellular targets of SAA-retinol complexes are unclear. In this study, we identified a receptor for SAA-retinol complexes that mediates retinol uptake into intestinal myeloid cells. Moreover, we determined how this retinol uptake mechanism affects vitamin A—dependent immunity. RESULTS Using biochemical approaches, including chemical cross-linking and mass spectrometry, we identified low-density lipoprotein (LDL) receptor—related protein 1 (LRP1) as a cell surface receptor for SAAs that binds SAA-retinol complexes with high affinity. We showed that LRP1 mediates cell surface binding and the endocytosis of SAA-retinol complexes in cultured cells. In the intestine, the highest levels of LRP1 expression were on CD11c+ myeloid cells, which efficiently bound SAA-retinol complexes, thereby internalizing retinol. The physiological roles of SAAs and their LRP1 receptor were identified in vivo using two mouse models: Saa−/− mice with a deletion of the entire Saa gene locus and Lrp1ΔCd11c mice with a myeloid cell–specific deletion of the Lrp1 gene. Studies of these mice revealed that SAAs and their LRP1 receptor facilitated retinol uptake by intestinal myeloid cells in vivo and promoted the expression of enzymes that convert retinol to RA. Accordingly, SAAs and myeloid cell LRP1 were required for the development of vitamin A—dependent adaptive immunity, including B and T cell homing to the intestine and IgA production. Finally, we found that SAAs and LRP1 promoted immunity to enteric infection after immunization. CONCLUSION We have identified SAAs as retinol-binding proteins that deliver retinol to RA-producing intestinal myeloid cells. SAA-retinol complexes bind to LRP1 on the myeloid cell surface and are endocytosed, providing retinol for the enzymatic generation of RA. Consequently, SAAs and LRP1 promote the development of vitamin A—dependent adaptive immunity in the intestine and enhance resistance to enteric infection after immunization. Our findings identify a mechanism by which retinol is acquired by intestinal myeloid cells and show that this mechanism promotes vitamin A—dependent intestinal adaptive immunity. Because expression of SAAs by intestinal epithelial cells requires the microbiota, our findings suggest that the microbiota promotes the development of adaptive immunity in part by regulating epithelial SAA expression. These findings also suggest that SAAs could deliver retinol to myeloid cells that reside in other tissues. By illuminating how vitamin A is mobilized to the intestinal immune system, our results may offer additional approaches for enhancing resistance to infection and for increasing the efficacy of mucosal vaccines, which depend on adequate dietary vitamin A. SAA proteins deliver retinol to intestinal myeloid cells through LRP1 to promote adaptive immunity. SAAs are retinol-binding proteins induced in intestinal epithelial cells by the microbiota and vitamin A. SAAs deliver retinol to retinoic acid? "producing myeloid cells by binding to the endocytic receptor LRP1. LRP1 and SAAs promote development of vitamin A? "dependent adaptive immunity in the intestine and enhance resistance to enteric infection. Vitamin A and its derivative retinol are essential for the development of intestinal adaptive immunity. Retinoic acid (RA)–producing myeloid cells are central to this process, but how myeloid cells acquire retinol for conversion to RA is unknown. Here, we show that serum amyloid A (SAA) proteins—retinol-binding proteins induced in intestinal epithelial cells by the microbiota—deliver retinol to myeloid cells. We identify low-density lipoprotein (LDL) receptor–related protein 1 (LRP1) as an SAA receptor that endocytoses SAA-retinol complexes and promotes retinol acquisition by RA-producing intestinal myeloid cells. Consequently, SAA and LRP1 are essential for vitamin A–dependent immunity, including B and T cell homing to the intestine and immunoglobulin A production. Our findings identify a key mechanism by which vitamin A promotes intestinal immunity.