Biomarkers and therapeutic targets: microRNA roles in the pathophysiology, diagnosis and management of eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease that is increasingly recognized as the cause of common gastrointestinal symptoms including dysphagia, chest and abdominal pain, heartburn, food impaction, and food refusal in children and adults. Often referred to as “asthma of the esophagus”, eosinophilic esophagitis, like its asthma counterpart, is an allergic disorder on the rise worldwide. Clinically managed by food avoidance, steroid therapy, recurring endoscopic evaluations and dilations as needed, eosinophilic esophagitis is a poorly understood disease process with limited therapies and even fewer diagnostic tools to predict and surveil active inflammation. As a result, there is a critical need to identify noninvasive biomarkers and therapeutic targets for eosinophilic esophagitis. Here we review the known contributions of miRNAs to eosinophilic inflammation of the esophagus and the potential for miRNA biomarkers for EoE in the clinical setting.

Keywords

Eosinophilic esophagitis / microRNA / miR-375 / miR-21 / miR-223 / biomarkers / miRNA replacement therapy

References

[1] DesaiTK,ChangCH,BadizadeganK.Association of eosinophilic inflammation with esophageal food impaction in adults.Gastrointest Endosc2005;61:795-801

[2] KerlinP,RemediosM.Prevalence of eosinophilic esophagitis in adults with food bolus obstruction of the esophagus.J Clin Gastroenterol2007;41:356-61

[3] SperrySL,MillerCB,DellonES.Esophageal foreign-body impactions: epidemiology, time trends, and the impact of the increasing prevalence of eosinophilic esophagitis.Gastrointest Endosc2011;74:985-91 PMCID:PMC3951006

[4] MaheshVN,NguyenNQ.Changing epidemiology of food bolus impaction: is eosinophilic esophagitis to blame?.J Gastroenterol Hepatol2013;28:963-6

[5] DellonES.Epidemiology and natural history of eosinophilic esophagitis.Gastroenterology2018;154:319-32.e3

[6] SimonD,SpergelJM,HolbreichM,RothenbergME,MuraroA,SchoepferA,SimonHU.Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity.Allergy2016;71:611-20

[7] DeBrosseCW.Allergy and eosinophil-associated gastrointestinal disorders (EGID)..Curr Opin Immunol2008;20:703-8 PMCID:PMC2615814

[8] SampsonHA,BockSA,JonesS,NadeauK,OppenheimerJ,RandolphC,SimonRA,WoodR,BernsteinD,KhanD,NicklasR,PortnoyJ,SchullerD,TillesSA,Practice Parameter Workshop,AcevesS,JamesJ,LangD,Nowak-WegrzynA,PerryTT,SichererSH,VickeryBP.Food allergy: a practice parameter update-2014.J Allergy Clin Immunol2014;134:1016-25.e43

[9] FoggMI,SpergelJM.Pollen and eosinophilic esophagitis.J Allergy Clin Immunol2003;112:796-7

[10] RayapudiM,ZhuX,AboniaJP,MishraA.Indoor insect allergens are potent inducers of experimental eosinophilic esophagitis in mice.J Leukoc Biol2010;88:337-46 PMCID:PMC2908938

[11] LucendoAJ,AriasA,BredenoordAJ,Amil DiasJ,Gonzalez-CerveraJ,MiehlkeS,Rodriguez-SanchezJ,RonkainenJ,SchoepferAM,TerreehorstI,AttwoodSE.Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.United European Gastroenterol J2017;5:335-58 PMCID:PMC5415218

[12] WechslerJB.Allergic mechanisms in eosinophilic esophagitis.Gastroenterol Clin North Am2014;43:281-96 PMCID:PMC4019969

[13] HillDA,RamosM.Eosinophilic esophagitis is a late manifestation of the atopic march.J Allergy Clin Immunol2018;

[14] HillDA.The immunologic mechanisms of eosinophilic esophagitis.Curr Allergy Asthma Rep2016;16:9 PMCID:PMC4913464

[15] O'SheaKM,DellonES,SpergelJM,RothenbergME.Pathophysiology of eosinophilic esophagitis.Gastroenterology2018;154:333-45

[16] MishraA,BrandtEB.An etiological role for aeroallergens and eosinophils in experimental esophagitis.J Clin Invest2001;107:83-90 PMCID:PMC198543

[17] FriedmanRC,BurgeCB.Most mammalian mRNAs are conserved targets of microRNAs.Genome Res2009;19:92-105 PMCID:PMC2612969

[18] CortezMA,FerdinJ,SoodAK.MicroRNAs in body fluids--the mix of hormones and biomarkers.Nat Rev Clin Oncol2011;8:467-77 PMCID:PMC3423224

[19] WeberJA,ZhangS,HuangKH,GalasDJ.The microRNA spectrum in 12 body fluids.Clin Chem2010;56:1733-41 PMCID:PMC4846276

[20] PanganibanRP,MaruSY,RoffAN.Differential microRNA epression in asthma and the role of miR-1248 in regulation of IL-5.Am J Clin Exp Immunol2012;1:154-65 PMCID:PMC3714196

[21] PanganibanRP,HowrylakJ,CraigTJ,IshmaelFT.Circulating microRNAs as biomarkers in patients with allergic rhinitis and asthma.J Allergy Clin Immunol2016;137:1423-32

[22] LuTX,RothenbergME.MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression.J Immunol2009;182:4994-5002 PMCID:PMC4280862

[23] LiuF,XuB,ZhaoDY.Profiling of miRNAs in pediatric asthma: upregulation of miRNA-221 and miRNA-485-3p.Mol Med Rep2012;6:1178-82

[24] SonkolyE,MajuriML,FyhrquistN,XuN,WeiT,StenvangJ,AleniusH,HomeyB,StahleM.MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4.J Allergy Clin Immunol2010;126:581-9.e1-20

[25] VennegaardMT,HagedornPH,LovendorfMB,WoetmannA,SkovL.Allergic contact dermatitis induces upregulation of identical microRNAs in humans and mice.Contact Dermatitis2012;67:298-305

[26] ShaoqingY,GuojunL,HuaH,JieZ.Microarray analysis of differentially expressed microRNAs in allergic rhinitis.Am J Rhinol Allergy2011;25:e242-6

[27] AttwoodSE,DemeesterTR.Esophageal eosinophilia with dysphagia.A distinct clinicopathologic syndrome. Dig Dis Sci1993;38:109-16

[28] BitonM,SlyperM,HorwitzE,Kredo-RussoS,CojocaruG,BentwichZ,ArtisD,HornsteinE,Ben-NeriahY.Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk.Nat Immunol2011;12:239-46

[29] McKennaLB,VourekasA,BramswigNC,KaestnerKH.MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function.Gastroenterology2010;139:1654-64.e1 PMCID:PMC3156097

[30] NakatoG,SatoT,SakakibaraS,ObataY,IwanagaT.Epithelium-intrinsic microRNAs contribute to mucosal immune homeostasis by promoting M-cell maturation.PLoS One2016;11:e0150379 PMCID:PMC4773159

[31] LuTX,WenT,HoganSP,AronowBJ.MiR-375 is downregulated in epithelial cells after IL-13 stimulation and regulates an IL-13-induced epithelial transcriptome.Mucosal Immunol2012;5:388-96 PMCID:PMC4154234

[32] LuTX,WenT,BesseJA,FranciosiJP,EbyM,AronowBJ.MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers.J Allergy Clin Immunol2012;129:1064-75.e9 PMCID:PMC3466056

[33] ZahmAM,BenitezAJ,Le GuenCL,FriedmanJR.Pediatric eosinophilic esophagitis is associated with changes in esophageal microRNAs.Am J Physiol Gastrointest Liver Physiol2014;307:G803-12 PMCID:PMC4200319

[34] DweepH.miRWalk2.0: a comprehensive atlas of microRNA-target interactions..Nat Methods2015;12:697

[35] AzouzNP,CaldwellJM,RochmanM,RayLM,MinglerMK,EilermanM,HeH,MukkadaVA,Khurana HersheyGK,WenT,RothenbergME.The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses.Sci Transl Med2018;10:eaap9736

[36] AnthiyaS,LoussouarnC,GarnettM,GarcionE.MicroRNA-based drugs for brain tumors.Trends Cancer2018;4:222-38

[37] GuoJ,GuiS.RNA interference-based nanosystems for inflammatory bowel disease therapy.Int J Nanomedicine2016;11:5287-310 PMCID:PMC5068481

[38] AcevesSS.Unmet therapeutic needs in eosinophilic esophagitis.Dig Dis2014;32:143-8 PMCID:PMC4037231

[39] LuS,MangrayS,ShillingfordN,BrodskyAS.MicroRNA profiling in mucosal biopsies of eosinophilic esophagitis patients pre and post treatment with steroids and relationship with mRNA targets.PLoS One2012;7:e40676 PMCID:PMC3398046

[40] KelbelTE,SenaM.Salivary microRNA as a biomarker for monitoring response to treatment in eosinophilic esophagitis.J Allergy Clin Immunol2015;135:AB78

[41] SwansonK,ShulmanR,HiremathG.Salivary microRNAs in eosinophilic esophagitis: pathobiologic implications and potential as noninvasive biomarker..Gastroenterology2016;150:S673-S4

[42] ShodaT,AcevesSS,AtkinsD,CaldwellJM,CarpenterCL,DellonES,GonsalvesN,FalkGW,Menard-KatcherP,KrischerJP,MukkadaVA,TrimarchiMP,ZimmermannN,RothenbergME.Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: a cross-sectional study.Lancet Gastroenterol Hepatol2018;3:477-88