Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18

Abstract

<jats:title>Abstract</jats:title><jats:p>Intestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to confer protection against pathogens. Here we show that IEC-intrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stop<jats:sup>ΔIEC</jats:sup>) showed significantly higher <jats:italic>Salmonella</jats:italic> burden in colonic tissues early in the infection associated with higher luminal and systemic loads of the pathogen at later stages. Higher susceptibility of stop<jats:sup>ΔIEC</jats:sup> mice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stop<jats:sup>ΔIEC</jats:sup> mice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stop<jats:sup>ΔIEC</jats:sup> mice restored resistance to <jats:italic>Salmonella</jats:italic> by promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response to <jats:italic>Salmonella</jats:italic> infection by regulating IL-18 production by IECs.</jats:p><jats:sec><jats:title>Author Summary</jats:title><jats:p>Epithelial cells line the intestinal lumen, forming a barrier between the body and dietary and microbial contents in the lumen. Apart from absorbing nutrients from diet, these epithelial cells help mediate a stable, symbiotic relationship between microbes in the gut and the immune cells. During infection, they help co-ordinate the immune response to counter the infection. How dietary micronutrients, such as vitamin A, inform epithelial cell function during infection is poorly understood. Using a model where epithelial cells in the gut cannot respond to vitamin A signals, we find that epithelial vitamin A signaling promotes resistance to <jats:italic>Salmonella</jats:italic> infection. We show that, vitamin A increases the production of a key cytokine, interleukin 18, by epithelial cells. IL-18 promotes shedding of infected epithelial cells to reduce the pathogen invasion while also inducing the production of interferon gamma by immune cells to mediate pathogen clearance. Thus, epithelial cells dynamically respond to dietary vitamin A to regulate interleukin 18 production and potentiate resistance to infection.</jats:p></jats:sec>

Commensal bacterial-derived retinoic acid primes host defense to intestinal infection

“…SFB and 16S bacterial levels were similar in dnRAR FF and dnRAR IEC mice (Figures 2E and 2F). Interestingly, dnRAR IEC mice exhibited significantly higher C. rodentium infection compared with floxed controls (dnRAR FF ) ( Figures 2G and 2H), a similar effect previously described for Salmonella typhimurium infection (Gattu et al, 2019;Iyer et al, 2020). To next decipher whether RA-driven protection requires epithelial RAR activation, control and dnRAR IEC mice were treated with RA and infected with C. rodentium.…”

“…Consistent with this, recent studies have discovered that IEC-intrinsic RAR expression promotes defense by regulating antimicrobial peptide production (Gattu et al, 2019;Jijon et al, 2018). Furthermore, the ability of IECs to sense RA is necessary for defense against Salmonella typhimurium (Gattu et al, 2019;Iyer et al, 2020).…”

“…The role of RA in infection has been most extensively investigated in immune cells (Hall et al, 2011a) and recent studies demonstrated that loss of RAR expression or impaired RAR responsiveness in IECs alters intestinal development and defense (Gattu et al, 2019;Iyer et al, 2020;Jijon et al, 2018). To test whether IEC-intrinsic RA signaling contributes to RA mediated protection against C. rodentium infection, we generated an IEC-specific dominant-negative RAR (dnRAR) transgenic mouse ( Figure 2C) that expresses non-responsive RAR specifically in IECs (dnRAR IEC ) ( Figure 2D).…”

Gut commensals expand vitamin A metabolic capacity of the mammalian host

“…Role of RA in maintaining a robust intestinal epithelium barrier is especially important in regulating host microbe interactions (Gattu et al, 2019;Snyder et al, 2020). Loss of intestinal epithelial cell (IEC) intrinsic RA signaling in mice results in defective goblet cell lineage commitment and reduced epithelial cell shedding upon infection (Iyer et al, 2020;Jijon et al, 2018). However, despite RA's critical role in regulating epithelial barrier, we observed that VA metabolic machinery and RA synthesis are suppressed by commensal bacteria, suggesting that IECs depend on an alternate source of RA (Grizotte-Lake et al, 2018).…”

Plant Kingdom as Source of Vitamins

“…A mechanistic explanation for the protective role of vitamin A derivatives in gut infection was recently brought: in a model of salmonella infection in mice, vitamin A stimulates IL-18 production, which acts both on early stages of infection (by promoting cell shedding, i.e., renewal of epithelial barrier and elimination of contaminated cells) and on later stages through Th1 and Th17 responses of immune cells and IFN-γ production, for pathogen clearance. Not surprisingly, this is a RARmediated transcriptional effect (Iyen et al 2020).…”