LRH-1/NR5A2 targets mitochondrial dynamics to reprogramtype 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype

Abstract

	•LRH-1/NR5A2 activation in inflammatory cells of individuals with type 1 diabetes (T1D) reduces pro-inflammatory cell surface markers and cytokine release.
	•LRH-1/NR5A2 promotes a mitohormesis-induced immuno-resistant phenotype to pro-inflammatory macrophages.
	•Mature dendritic cells acquire a tolerogenic phenotype via LRH-1/NR5A2-stimulated mitochondria turnover.
	•LRH-1/NR5A2 agonistic activation expands a CD4+/CD25+/FoxP3+ T-cell subpopulation.
	•Pharmacological activation of LRH-1/NR5A2 improves the survival iPSC-islets-like organoids co-cultured with PBMCs from individuals with T1D.

Keywords

autoimmune diseases / drug development / immune tolerance / pancreatic islets

References

[1] WardZJ, YehJM, ReddyCL, et al. Estimating the total incidence of type 1 diabetes in children and adolescents aged 0–19 years from 1990 to 2050: a global simulation-based analysis. Lancet Diabetes Endocrinol. 2022; 10(12): 848-858.

[2] HeroldKC, DelongT, PerdigotoAL, Biru N, BruskoTM, WalkerLSK. The immunology of type 1 diabetes. Nat Rev Immunol. 2024; 24(6): 435-451.

[3] DiMeglioLA, Evans-Molina C, OramRA. Type 1 diabetes. Lancet. 2018; 391(10138): 2449-2462.

[4] EizirikDL, Sammeth M, BouckenoogheT, et al. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet. 2012; 8(3): e1002552.

[5] SzymczakF, ColliML, MamulaMJ, Evans-Molina C, EizirikDL. Gene expression signatures of target tissues in type 1 diabetes, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. Sci Adv. 2021; 7(2): eabd7600.

[6] MalloneR, Eizirik DL. Presumption of innocence for beta cells: why are they vulnerable autoimmune targets in type 1 diabetes?. Diabetologia. 2020; 63(10): 1999-2006.

[7] TorenE, Burnette KS, BanerjeeRR, HunterCS, TseHM. Partners in crime: beta-cells and autoimmune responses complicit in type 1 diabetes pathogenesis. Front Immunol. 2021; 12: 756548.

[8] PinerosAR, Kulkarni A, GaoH, et al. Proinflammatory signaling in islet beta cells propagates invasion of pathogenic immune cells in autoimmune diabetes. Cell Rep. 2022; 39(13): 111011.

[9] Cobo-VuilleumierN, Gauthier BR. Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration. Metabolism. 2020; 104: 154137.

[10] FrigoDE, Bondesson M, WilliamsC. Nuclear receptors: from molecular mechanisms to therapeutics. Essays Biochem. 2021; 65(6): 847-856.

[11] WeikumER, LiuX, OrtlundEA. The nuclear receptor superfamily: a structural perspective. Protein Sci. 2018; 27(11): 1876-1892.

[12] ZhaoL, ZhouS, GustafssonJA. Nuclear receptors: recent drug discovery for cancer therapies. Endocr Rev. 2019; 40(5): 1207-1249.

[13] NadolnyC, DongX. Liver receptor homolog-1 (LRH-1): a potential therapeutic target for cancer. Cancer Biol Ther. 2015; 16(7): 997-1004.

[14] BaquieM, St-Onge L, Kerr-ConteJ, et al. The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects {beta}-cells against stress-induced apoptosis. Hum Mol Genet. 2011; 20: 2823-2833.

[15] LeeJM, LeeYK, MamroshJL, et al. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature. 2011; 474(7352): 506-510.

[16] MengL, DongF, DengJ. NR5A2 as a potential target for exercise to improve metabolic syndrome. Aging (Albany NY). 2023; 15(7): 2485-2502.

[17] MichalekS, Brunner T. Nuclear-mitochondrial crosstalk: on the role of the nuclear receptor liver receptor homolog-1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer. IUBMB Life. 2021; 73(3): 592-610.

[18] WuT, LuZF, YuHN, WuXS, LiuY, XuY. Liver receptor homolog-1: structures, related diseases, and drug discovery. Acta Pharmacol Sin. 2024; 45(8): 1571-1581.

[19] Cobo-VuilleumierN, Lorenzo PI, RodriguezNG, et al. LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus. Nat Commun. 2018; 9(1): 1488.

[20] Martin VázquezE, Cobo-Vuilleumier N, Araujo LegidoR, et al. NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function. iScience. 2022; 25(5): 104345.

[21] Martín-VázquezE, Cobo-VuilleumierN, López-Noriega L, LorenzoPI, GauthierBR. The PTGS2/COX2-PGE2 signaling cascade in inflammation: pro or anti? A case study with type 1 diabetes mellitus. Int J Biol Sci. 2023; 19(13): 4157-4165.

[22] LefevreL, Authier H, SteinS, et al. LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARgamma ligand synthesis. Nat Commun. 2015; 6: 6801.

[23] SchwadererJ, GaiserAK, PhanTS, Delgado ME, BrunnerT. Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions. Cell Death Dis. 2017; 8(4): e2745.

[24] SeitzC, HuangJ, GeiselhoringerAL, et al. The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions. Sci Adv. 2019; 5(7): eaav9732.

[25] AhmedM, de Winther MPJ, Van den BosscheJ. Epigenetic mechanisms of macrophage activation in type 2 diabetes. Immunobiology. 2017; 222(10): 937-943.

[26] Di MarcoE, GraySP, Jandeleit-DahmK. Diabetes alters activation and repression of pro-and anti-inflammatory signaling pathways in the vasculature. Front Endocrinol (Lausanne). 2013; 4: 68.

[27] DanovaK, Grohova A, StrnadovaP, et al. Tolerogenic dendritic cells from poorly compensated type 1 diabetes patients have decreased ability to induce stable antigen-specific T cell hyporesponsiveness and generation of suppressive regulatory T cells. J Immunol. 2017; 198(2): 729-740.

[28] LytriviM, SeneeV, SalpeaP, et al. DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes. Eur J Endocrinol. 2021; 184(3): 455-468.

[29] De FrancoE, Lytrivi M, IbrahimH, et al. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress. J Clin Invest. 2020; 130(12): 6338-6353.

[30] DemineS, Schiavo AA, Marin-CanasS, MarchettiP, CnopM, EizirikDL. Pro-inflammatory cytokines induce cell death, inflammatory responses, and endoplasmic reticulum stress in human iPSC-derived beta cells. Stem Cell Res Ther. 2020; 11(1): 7.

[31] Igoillo-EsteveM, Oliveira AF, CosentinoC, et al. Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia. JCI Insight. 2020; 5(2): e134221.

[32] FantuzziF, Toivonen S, SchiavoAA, et al. In depth functional characterization of human induced pluripotent 1 stem cell-derived beta cells in vitro and in vivo. Frontiers Cell Dev Biol. 2022; 10: 967765.

[33] RappsilberJ, MannM, IshihamaY. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc. 2007; 2(8): 1896-1906.

[34] Salas-LloretD, Agabitini G, Gonzalez-PrietoR. TULIP2: an improved method for the identification of ubiquitin E3-specific targets. Front Chem. 2019; 7: 802.

[35] TyanovaS, TemuT, CoxJ. The MaxQuant computational platform for mass spectrometry-based shotgun proteomics. Nat Protoc. 2016; 11(12): 2301-2319.

[36] Salas-LloretD, Garcia-Rodriguez N, Soto-HidalgoE, et al. BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis. Nat Commun. 2024; 15(1): 4292.

[37] DemichevV, Szyrwiel L, YuF, et al. dia-PASEF data analysis using FragPipe and DIA-NN for deep proteomics of low sample amounts. Nat Commun. 2022; 13(1): 3944.

[38] DemichevV, Messner CB, VernardisSI, LilleyKS, RalserM. DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput. Nat Methods. 2020; 17(1): 41-44.

[39] TyanovaS, TemuT, SinitcynP, et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods. 2016; 13(9): 731-740.

[40] GoedhartJ, Luijsterburg MS. VolcaNoseR is a web app for creating, exploring, labeling and sharing volcano plots. Sci Rep. 2020; 10(1): 20560.

[41] SzklarczykD, GableAL, LyonD, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019; 47(D1): D607-D613.

[42] ShannonP, Markiel A, OzierO, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11): 2498-2504.

[43] TangD, ChenM, HuangX, et al. SRplot: a free online platform for data visualization and graphing. PLoS One. 2023; 18(11): e0294236.

[44] NandakumarMP, ShenJ, RamanB, Marten MR. Solubilization of trichloroacetic acid (TCA) precipitated microbial proteins via naOH for two-dimensional electrophoresis. J Proteome Res. 2003; 2(1): 89-93.

[45] Lopez-NoriegaL, Capilla-Gonzalez V, Cobo-VuilleumierN, et al. Inadequate control of thyroid hormones sensitizes to hepatocarcinogenesis and unhealthy aging. Aging (Albany NY). 2019; 11: 7746-7779.

[46] MonteiroLB, Davanzo GG, de AguiarCF, Moraes-VieiraPMM. Using flow cytometry for mitochondrial assays. MethodsX. 2020; 7: 100938.

[47] HounkpeBW, ChenouF, de LimaF, De Paula EV. HRT Atlas v1.0 database: redefining human and mouse housekeeping genes and candidate reference transcripts by mining massive RNA-seq datasets. Nucleic Acids Res. 2021; 49(D1): D947-D955.

[48] Mellado-GilJM, Fuente-Martin E, LorenzoPI, et al. The type 2 diabetes-associated HMG20A gene is mandatory for islet beta cell functional maturity. Cell Death Dis. 2018; 9(3): 279.

[49] Rodriguez-FernandezS, Pujol-Autonell I, BriansoF, et al. Phosphatidylserine-liposomes promote tolerogenic features on dendritic cells in human type 1 diabetes by apoptotic mimicry. Front Immunol. 2018; 9: 253.

[50] KellyA, Grabiec AM, TravisMA. Culture of human monocyte-derived macrophages. Methods Mol Biol. 2018; 1784: 1-11.

[51] XuanW, QuQ, ZhengB, Xiong S, FanGH. The chemotaxis of M1 and M2 macrophages is regulated by different chemokines. J Leukoc Biol. 2015; 97(1): 61-69.

[52] FlachM, Diefenbach A. Chapter 3 -Development of gut-associated lymphoid tissues. In: Mestecky J, Strober W, Russell MW, Kelsall BL, Cheroutre H, Lambrecht BN, eds. Mucosal Immunology. 4th ed. Academic Press; 2015: 31-42.

[53] YunnaC, MengruH, LeiW, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol. 2020; 877: 173090.

[54] ShenL, LiY, ZhaoH. Fibroblast growth factor signaling in macrophage polarization: impact on health and diseases. Front Immunol. 2024; 15: 1390453.

[55] WhiteGE, IqbalAJ, GreavesDR. CC chemokine receptors and chronic inflammation–therapeutic opportunities and pharmacological challenges. Pharmacol Rev. 2013; 65(1): 47-89.

[56] LindnerM, Thummler K, ArthurA, et al. Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9. Brain. 2015; 138(Pt 7): 1875-1893.

[57] MattioliB, Straface E, QuarantaMG, GiordaniL, VioraM. Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming. J Immunol. 2005; 174(11): 6820-6828.

[58] FelixFB, DiasJ, VagoJP, et al. Blocking the HGF-MET pathway induces resolution of neutrophilic inflammation by promoting neutrophil apoptosis and efferocytosis. Pharmacol Res. 2023; 188: 106640.

[59] BaoW, BusselJB, HeckS, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010; 116(22): 4639-4645.

[60] MaoYM, ZhaoCN, LengJ, et al. Interleukin-13: a promising therapeutic target for autoimmune disease. Cytokine Growth Factor Rev. 2019; 45: 9-23.

[61] AzeemW, BakkeRM, AppelS, Oyan AM, KallandKH. Dual pro-and anti-inflammatory features of monocyte-derived dendritic cells. Front Immunol. 2020; 11: 438.

[62] LiuM, BaiJ, HeS, et al. Grb10 promotes lipolysis and thermogenesis by phosphorylation-dependent feedback inhibition of mTORC1. Cell Metab. 2014; 19(6): 967-980.

[63] IpWKE, HoshiN, ShouvalDS, Snapper S, MedzhitovR. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017; 356(6337): 513-519.

[64] YuanY, ChenY, PengT, et al. Mitochondrial ROS-induced lysosomal dysfunction impairs autophagic flux and contributes to M1 macrophage polarization in a diabetic condition. Clin Sci (Lond). 2019; 133(15): 1759-1777.

[65] BuneAJ, HaymanAR, EvansMJ, Cox TM. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disordered macrophage inflammatory responses and reduced clearance of the pathogen, Staphylococcus aureus. Immunology. 2001; 102(1): 103-113.

[66] Ledesma-ColungaMG, Baschant U, WeidnerH, et al. Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis. Redox Biol. 2023; 60: 102616.

[67] MatsudaA, SuzukiY, HondaG, et al. Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. Oncogene. 2003; 22(21): 3307-3318.

[68] LinL, ChenS, WangH, et al. SPTBN1 inhibits inflammatory responses and hepatocarcinogenesis via the stabilization of SOCS1 and downregulation of p65 in hepatocellular carcinoma. Theranostics. 2021; 11(9): 4232-4250.

[69] ZanoniI, OstuniR, MarekLR, et al. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell. 2011; 147(4): 868-880.

[70] CiesielskaA, Matyjek M, KwiatkowskaK. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cell Mol Life Sci. 2021; 78(4): 1233-1261.

[71] CuschieriJ, Gourlay D, GarciaI, JelacicS, MaierRV. Implications of proteasome inhibition: an enhanced macrophage phenotype. Cell Immunol. 2004; 227(2): 140-147.

[72] ChoiS, DongB, LinCJ, et al. Methyl-sensing nuclear receptor liver receptor homolog-1 regulates mitochondrial function in mouse hepatocytes. Hepatology. 2020; 71(3): 1055-1069.

[73] SharyginD, Koniaris LG, WellsC, ZimmersTA, HamidiT. Role of CD14 in human disease. Immunology. 2023; 169(3): 260-270.

[74] LauterbachMA, HankeJE, SerefidouM, et al. Toll-like receptor signaling rewires macrophage metabolism and promotes histone acetylation via ATP-citrate lyase. Immunity. 2019; 51(6): 997-1011.e1017.

[75] MillsEL, KellyB, LoganA, et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. 2016; 167(2): 457-470.e413.

[76] BarcenaC, Mayoral P, QuirosPM. Mitohormesis, an antiaging paradigm. Int Rev Cell Mol Biol. 2018; 340: 35-77.

[77] TimblinGA, TharpKM, FordB, et al. Mitohormesis reprogrammes macrophage metabolism to enforce tolerance. Nat Metab. 2021; 3(5): 618-635.

[78] FuJ, Schroder K, WuH. Mechanistic insights from inflammasome structures. Nat Rev Immunol. 2024; 24(7): 518-535.

[79] PozziLA, Maciaszek JW, RockKL. Both dendritic cells and macrophages can stimulate naive CD8 T cells in vivo to proliferate, develop effector function, and differentiate into memory cells. J Immunol. 2005; 175(4): 2071-2081.

[80] NairS, Buiting AM, RouseRJ, Van RooijenN, HuangL, RouseBT. Role of macrophages and dendritic cells in primary cytotoxic T lymphocyte responses. Int Immunol. 1995; 7(4): 679-688.

[81] KellyB, O’Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015; 25(7): 771-784.

[82] ComiM, Avancini D, de SioFS, et al. Coexpression of CD163 and CD141 identifies human circulating IL-10-producing dendritic cells (DC-10). Cell Mol Immunol. 2020; 17(1): 95-107.

[83] Beydag-TasozBS, YennekS, Grapin-BottonA. Towards a better understanding of diabetes mellitus using organoid models. Nat Rev Endocrinol. 2023; 19(4): 232-248.

[84] de BracheneAC, Alvelos MI, SzymczakF, et al. Interferons are key cytokines acting on pancreatic islets in type 1 diabetes. Diabetologia. 2024; 67(5): 908-927.

[85] EizirikDL, Pasquali L, CnopM. Pancreatic beta-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol. 2020; 16(7): 349-362.

[86] PennaG, Adorini L. 1 Alpha, 25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol. 2000; 164(5): 2405-2411.

[87] van HalterenAG, van Etten E, de JongEC, BouillonR, RoepBO, MathieuC. Redirection of human autoreactive T-cells Upon interaction with dendritic cells modulated by TX527, an analog of 1, 25 dihydroxyvitamin D(3). Diabetes. 2002; 51(7): 2119-2125.

[88] Van den BosscheJ, Baardman J, OttoNA, et al. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep. 2016; 17(3): 684-696.

[89] PatsalosA, HalaszL, Medina-SerpasMA, et al. A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15. J Exp Med. 2022; 219(1): e20210420.

[90] NakayasuES, SyedF, TerseySA, et al. Comprehensive proteomics analysis of stressed human islets identifies GDF15 as a target for type 1 diabetes intervention. Cell Metab. 2020; 31(2): 363-374.e366.

[91] VeithAP, Henderson K, SpencerA, SligarAD, BakerAB. Therapeutic strategies for enhancing angiogenesis in wound healing. Adv Drug Deliv Rev. 2019; 146: 97-125.

[92] SchleckerE, Stojanovic A, EisenC, et al. Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth. J Immunol. 2012; 189(12): 5602-5611.

[93] LuCC, TsaiHC, YangDY, et al. The chemokine CCL4 stimulates angiopoietin-2 expression and angiogenesis via the MEK/ERK/STAT3 pathway in oral squamous cell carcinoma. Biomedicines. 2022; 10(7): 1612.

[94] YamasakiS, IvanovP, HuGF, Anderson P. Angiogenin cleaves tRNA and promotes stress-induced translational repression. J Cell Biol. 2009; 185(1): 35-42.

[95] CzechA, WendeS, MorlM, Pan T, IgnatovaZ. Reversible and rapid transfer-RNA deactivation as a mechanism of translational repression in stress. PLoS Genet. 2013; 9(8): e1003767.

[96] Van SickleBJ, Simmons J, HallR, RainesM, NessK, SpagnoliA. Increased circulating IL-8 is associated with reduced IGF-1 and related to poor metabolic control in adolescents with type 1 diabetes mellitus. Cytokine. 2009; 48(3): 290-294.

[97] PenarandaC, Kuswanto W, HofmannJ, et al. IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells. Proc Natl Acad Sci U S A. 2012; 109(31): 12668-12673.

[98] LeeLF, Logronio K, TuGH, et al. Anti-IL-7 receptor-alpha reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function. Proc Natl Acad Sci U S A. 2012; 109(31): 12674-12679.

[99] HeroldKC, Bucktrout SL, WangX, et al. Immunomodulatory activity of humanized anti-IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes. JCI Insight. 2019; 4(24): e126054.

[100] HarrisJ, DeenN, ZamaniS, Hasnat MA. Mitophagy and the release of inflammatory cytokines. Mitochondrion. 2018; 41: 2-8.

[101] GeartySV, DundarF, ZumboP, et al. An autoimmune stem-like CD8 T cell population drives type 1 diabetes. Nature. 2022; 602(7895): 156-161.

[102] SchwadererJ, PhanTS, GlocknerA, et al. Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis. Cell Death Dis. 2020; 11(2): 154.

[103] LambrechtR, Delgado ME, GloeV, et al. Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death. Cell Rep. 2023; 42(12): 113513.

[104] Perez-RiverolY, BaiJ, BandlaC, et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 2022; 50(D1): D543-D552.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.