Benson

Biburger

Coombes

Curotto de Lafaille

Duester

Guilliams

Hall

Iwata

Kang

Labbaye

Mehta

Mora

Mucida

Nagy

Pino-Lagos

Szatmari

Takeda

Tiegs

Toyabe

Tsai

Underwood

Wang

Yamada

Nagy, László

Repository of the Academy's Library

Eur. J. Immunol. 2012. 42: 1677–1680 HIGHLIGHTSDOI: 10.1002/eji.201242705 1677CommentryWould eating carrots protect your liver? A new roleinvolving NKT cells for retinoic acid in hepatitisLaszlo Nagy1,21 Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine,University of Debrecen, Medical and Health Science Center, Debrecen, Hungary2 MTA-DE “Lendu¨let” Immunogenomics Research Group, Medical and Health Science Center,University of Debrecen, Debrecen, HungaryRetinoic acid (RA), which is the biologically active form of vitamin A, acts through thenuclear hormone receptor RAR (RA receptor) to induce either gene activation or repres-sion. RA production and its effects have been linked tomacrophages, dendritic cells, T andB cells, and iNKT cells in the immune system and play pro- as well as anti-inflammatoryroles depending on the cell type and the immune context. In this issue of the EuropeanJournal of Immunology, Lee et al. [Eur. J. Immunol. 2012. 42: 1685–1694] show that RA ame-liorates Con A-induced murine hepatitis by selectively downmodulating IFN-γ and IL-4production in disease-causing NKT cells in the liver. Remarkably, this effect is restrictedto this liver disease model and does not apply to αGalCer-induced murine liver injury,which is driven by other cytokines. The study identifies retinoid signaling as an importantendogenous mechanism controlling immune reactions and also as a potential pharma-cological target for treatment of hepatic liver injury. Furthermore, the study by Lee et al.provides additional support for the concept of metabolic regulation of immune function.Keywords: Hepatitis  NKT cells  Retinoids  RARSee accompanying article by Lee et al.Presently there is an increased understanding and appreciationof the role that metabolic and lipid signaling plays in immuneregulatory processes in multiple cell types (reviewed in [1]). Forexample, the orange pigment of carrots, beta-carotene, contributesto vitamin A levels in the body. Vitamin A is further processedinto retinol, which is taken up by cells and oxidized into reti-naldehyde by retinol dehydrogenase (alcohol dehydrogenase);retinaldehyde is subsequently oxidized by retinaldehyde dehydro-genase (RALDH) into retinoic acid (RA) (reviewed in [2]). RA(all-trans retinoic acid, RA) is one of the key biologically activecompounds of vitamin A, the other (11-cis retinal) is involved invision.Correspondence: Dr. Laszlo Nagye-mail: nagyl@med.unideb.huRA acts as a ligand for one of the members of the nuclear hor-mone receptor superfamily, namely the RAR:RXR (RA receptor:retinoid X receptor) heterodimer [1]. In the absence of ligand,this receptor heterodimer binds to specific regulatory regions,termed response elements, of genes in the genome and repressestheir transcription. Upon ligand binding, the receptor heterodimerbecomes activated and typically increases transcription [1,3]. Inaddition, the ligand-bound receptor can also bind to other tran-scription factors (e.g. NF-κB, AP1) via protein–protein interactionswithout directly binding to DNA, and by doing so can interferewith(i.e. repress) the transcriptional activity of these factors. This phe-nomenon is termed transrepression and is particularly importantin the control of inflammation [1]. Therefore, the production anddegradation of RA has to be very tightly regulated in order to coor-dinate its activating/inhibitory activities in the various cell typesand tissues on which it acts. One of the functions of the RAR:RXRheterodimer is to turn on the degradation of RA by activating theC© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1678 Laszlo Nagy Eur. J. Immunol. 2012. 42: 1677–1680expression of a p450 enzyme CYP26 [3], thus forming a feedbackloop to control RA actions.The cellular activities of RA are widespread. It regulatescell proliferation and differentiation in many cancer cell lines,keratinocytes aswell as cells of the immune system such asmyeloidcells (reviewed in [1,4]). These activities were typically identifiedby using exogenous, often synthetic activators or antagonists ofRAR [1]. However, there is validation of these somewhat “artificialsystems” since it is also well established that endogenous retinoidshave immunomodulatory effects. For example, vitamin A defi-ciency increases childhood mortality and morbidity and increasesan individual’s susceptibility to infectious diseases (reviewed in[5]). In addition, there have been a large number of studies onthe role of RA and/or RAR in hematopoietic differentiation andfunction. Of note, RAR is known to be expressed in nearly allhematopoietic lineages and to have roles in early myeloid differ-entiation and granulopoiesis [6,7]. RA has a dual effect on differ-entiation by either inducing maturation or cell death, dependingon the cellular context. It also blocks erythroid differentiation bydownregulating GATA-1 [8].Importantly, there is evidence for both pro- and anti-inflammatory activities of RA in macrophages. Regarding its anti-inflammatory actions, it has been documented that RA inhibitsnitric oxide and TNF production in peritoneal macrophages [9],and that it enhances IL-10 production and reduces TNF-α andIL-12 production in LPS-stimulated macrophages [10,11]. On thepro-inflammatory side, in rats treated with RA, the severity of TBinfection is reduced, and this is accompanied by an increase inNK-cell, T-cell, and macrophage numbers in organs such as thelung and spleen, along with increased levels of TNF-α, IFN-γ, andIL-1β [12]. These data clearly show that, when assessing the roleof retinoid signaling, context really matters.One of the most striking examples of tissue and cell type spe-cific production and activity of RA has been discovered by study-ing intestinal dendritic cells (DCs). Iwata et al. have shown thatDCs isolated from mesenteric lymph nodes and Peyer’s patches ofthe murine intestine are able to produce RA, also showing thatthese cells have the necessary enzymes (alcohol dehydrogenaseIII and Raldh2) to convert retinol to RA [13]. The CD103+ DCsubset is capable of inducing robust Treg-cell development [14].Synthetic antagonists of RAR efficiently blocked Treg-cell develop-ment [14]. Since then, additional DC subtypes located in the skinand lung have been shown to produce RA, suggesting that thisactivity might not be restricted to gut DCs [15]. A key develop-ment based on these findings was the dissection of the mechanismof gut-specific lymphocyte imprinting and oral tolerance and theinvolvement of RA. Of note with regard to gut-specific lympho-cyte imprinting, Iwata et al. showed that T cells primed with RAshowed preferential homing to the gut, that the expression of theα4β7 integrin and CCR9 on the T cells was essential for this hom-ing, and that RA induced α4β7 integrin and CCR9 expression inT lymphocytes [13]. Importantly, in the CD103+ DCs, blockingRAR led to the inhibition of the induction of gut homing recep-tors (CCR9 and α4β7) [13]. In addition, DC-derived RA has alsobeen shown to be important for B-cell gut tropism and IgA pro-duction [16,17]. Furthermore, in human monocyte derived DCsinduction of endogenous RA production leads to increased CD1dand reduced CD1a expression and a complete rearrangement oflipid antigen-presenting capacity, favoring iNKT activation [18].Regarding the role for RA in oral tolerance, it has been shownthat inducible Treg (iTreg) cells have an important role in main-taining tolerance and that gut CD103+ DC-derived RA elicits iTreg-cell development in synergy with TGF-β [14,19,20]. As far as themolecularmechanism is concerned, RAR has been shown to induceactive histone marks on the promoter of FoxP3, a master regula-tor of Treg-cell development, and hence to drive FoxP3 expression[21,22]. RA also blocks the IL-6- and TGF-β-driven induction ofthe pro-inflammatory IL-17-producing T (Th17) cells [23].But here again RA has Janus’s two faces, because it has beenshown that RA is also required for provoking a pro-inflammatoryT-cell response to mucosal vaccination and infection [24]; inhi-bition of RARα in T cells resulted in a cell autonomous CD4+T-cell activation defect [24]. Collectively, these data suggest thatendogenously produced RA is critical in shaping T-cell responses,but its effects are complex and difficult to untangle using onlypharmacological and cellular immunological methods. In vivostudies complemented with tissue-specific genetic ablation ofeither the receptor or key metabolic enzymes are required to gainfurther insight.A new wrinkle is added to these complex roles in this issueof the European Journal of Immunology by Lee et al. [25], whouse RA pretreatment to assess the contribution of retinoid sig-naling to immune-driven liver damage using two in vivo modelsof hepatitis. One model uses concanavalin A (Con A) to inducerapid T-cell, granulocyte, and Kupffer cell infiltration in the liver,leading to hepatocyte death and eventually the death of the ani-mal [26]. This model is believed to depend on NKT-cell activ-ity; NKT cells in this model produce large amounts of cytokines,such as IFN-γ, IL-4, and TNF-α, leading to hepatocyte damage[27,28]. While animals injected with Con A all died after 6 h,mice pretreated with RA all survived for at least 24 h [24]. Thisremarkable difference is accompanied by reduced levels of IFN-γand IL-4, but no change in TNF-α levels [24]. Using a pharma-cological inhibitor of RA synthesis (Disulfiram), the authors alsoshowed that the reduction of endogenous RA production couldaggravate Con A-induced hepatitis. By excluding the participa-tion of other cell types, such as Kupffer cells and Treg cells,and also by excluding changes in the activation of NKT cells perse, they pinpointed the changes in cytokine production as thecause of the in vivo phenotype. Remarkably, in the other modelof NKT cell driven hepatitis, RA pretreatment was ineffective. Inthis model, αGalCer, the ligand of CD1d, was administered toinduce hepatic tissue damage [29]. However, this model dependson FasL and TNF-α rather than IFN-γ, and while the RA-inducedchanges in cytokines were similar to those induced in the ConA model (i.e. reduced levels of IFN-γ and IL-4, but no changein TNF-α levels), this did not translate into a marked phenotypein α-GalCer-induced liver injury as these cytokines are not thephenotype drivers. As far as the mechanisms behind these find-ing are concerned, the authors propose that RA downregulatesC© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.euEur. J. Immunol. 2012. 42: 1677–1680 HIGHLIGHTS 1679Figure 1. RA selectively regulates cytokine production in NKT cells.The left side of the figure shows the metabolic steps leading to all trans-RA production and degradation. The enzymatic step inhibited bythe synthetic enzyme inhibitor, Disulfiram, a compound inhibiting acetaldehyde dehydrogenase and retinaldehyde dehydrogenase as well isindicated. All trans-RA directly binds to and activates the RAR:RXR heterodimeric receptor, which activates (arrow) or represses (blunt arrow) theindicated genes expression in the various indicated cell types. The list is partial and is intended only to illustrate the variety of effects RA has onvarious immune cells. The new activity identified by Lee et al. in this issue of the European Journal of Immunology [25] is marked by a box.IFN-γ and IL-4 production by a MAPK-dependent mechanism,while the NFAT-dependent TNF-α induction would be unaltered,hence explaining the differential effect on cytokine production(Fig. 1).These new data are important as they strongly implicate RAand, critically, its endogenous production, in the control of NKT-cell cytokine production and, by doing so, provide new pharmaco-logical targets for controlling hepatic inflammation in vivo. Thesefindings also provide support for the concept that lipid signaling,metabolism, and diet are important in the immune regulation ofT-cell subpopulations. Finally, they also highlight the need for fur-ther research into themechanistic details of the pathophysiologicaland gene regulatory events triggered by RA that, hopefully, willlead to further therapeutic targets for the regulation of inflamma-tion.Acknowledgement: Work in the author’s laboratory is supportedby grants from the Hungarian Scientific Research Fund (OTKANK72730 and K100196), EU FP7 (MOLMEDREX FP7-REGPOT-2008-1. #229920), and TAMOP-4.2.2/08/1, TA´MOP-4.2.1/B-09/1/KONV-2010-0007 implemented through the New Hun-gary Development Plan co-financed by the European Social Fundand the European Regional Development Fund.Conflict of Interest: The author declares no financial or commer-cial conflict of interest.References1 Nagy, L., Szanto, A., Szatmari, I.and Szeles, L., Nuclear hormone recep-tors enable macrophages and dendritic cells to sense their lipid environ-ment and shape their immune response. Physiol. 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USA 2000. 97: 5498–5503.28 Toyabe, S., Seki, S., Iiai, T., Takeda, K., Shirai, K., Watanabe, H.,Hiraide, H. et al., Requirement of IL-4 and liver NK1+ T cells for con-canavalin A-induced hepatic injury in mice. J. Immunol. 1997. 159: 1537–1542.29 Biburger, M.and Tiegs, G., Alpha-galactosylceramide-induced liverinjury in mice is mediated by TNF-alpha but independent of Kupffercells. J. Immunol. 2005. 175: 1540–1550.Abbreviation: RA: retinoic acidFull correspondence: Dr. Laszlo Nagy, Department of Biochemistry andMolecular Biology, University of Debrecen, Medical and Health ScienceCenter, Egyetem te´r 1. Debrecen, H-4010, HungaryFax: +36-52314989e-mail: nagyl@med.unideb.huSee accompanying article:http://dx.doi.org/10.1002/eji.201142322Received: 28/5/2012Revised: 1/6/2012Accepted: 1/6/2012C© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu

Would eating carotts protect your liver? A new role involving NKT cells for retinoic acid in hepatitis

Laszlo Nagy

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European Journal of Immunology

Would eating carrots protect your liver? A new role involving NKT cells for retinoic acid in hepatitis

Would eating carotts protect your liver? A new role involving NKT cells for retinoic acid in hepatitis

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