Proteasome inhibition promotes Foxn1 expression in thymic epithelial cells and induces thymic regeneration in mice

Proteasome inhibition promotes Foxn1 expression in thymic epithelial cells and induces thymic regeneration in mice

  • Anderson G, Jenkinson EJ. Lymphostromal interactions in thymic development and function. Nat Rev Immunol. 2001;1:31–40.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Takahama Y. Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol. 2006;6:127–35.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Petrie HT, Zúñiga-Pflücker JC. Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu Rev Immunol. 2007;25:649–79.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rosichini M, Bordoni V, Silvestris DA, Mariotti D, Matusali G, Cardinale A, et al. SARS-CoV-2 infection of thymus induces loss of function that correlates with disease severity. J Allergy Clin Immunol. 2023;151:911–21.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Velardi E, Clave E, Arruda LCM, Benini F, Locatelli F, Toubert A. The role of the thymus in allogeneic bone marrow transplantation and the recovery of the peripheral T-cell compartment. Semin Immunopathol. 2021;43:101–17.

    Article 
    PubMed 

    Google Scholar
     

  • Velardi E, Tsai JJ, van den Brink MRM. T cell regeneration after immunological injury. Nat Rev Immunol. 2021;21:277–91.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Komanduri KV, St John LS, De Lima M, McMannis J, Rosinski S, McNiece I, et al. Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing. Blood. 2007;110:4543–51.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Clave E, Lisini D, Douay C, Giorgiani G, Busson M, Zecca M, et al. A low thymic function is associated with leukemia relapse in children given T-cell-depleted HLA-haploidentical stem cell transplantation. Leukemia. 2012;26:1886–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Söderström A, Vonlanthen S, Jönsson-Videsäter K, Mielke S, Lindahl H, Törlén J, et al. T cell receptor excision circles are potential predictors of survival in adult allogeneic hematopoietic stem cell transplantation recipients with acute myeloid leukemia. Front Immunol. 2022;13:954716.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Troullioud Lucas AG, Lindemans CA, Bhoopalan SV, Dandis R, Prockop SE, Naik S, et al. Early immune reconstitution as predictor for outcomes after allogeneic hematopoietic cell transplant; a tri-institutional analysis. Cytotherapy. 2023;25:977–85.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goldberg JD, Zheng J, Ratan R, Small TN, Lai K-C, Boulad F, et al. Early recovery of T-cell function predicts improved survival after T-cell depleted allogeneic transplant. Leuk Lymphoma. 2017;58:1859–71.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bartelink IH, Belitser SV, Knibbe CAJ, Danhof M, De Pagter AJ, Egberts TCG, et al. Immune reconstitution kinetics as an early predictor for mortality using various hematopoietic stem cell sources in children. Biol Blood Marrow Transpl. 2013;19:305–13.

    Article 

    Google Scholar
     

  • Admiraal R, Chiesa R, Lindemans CA, Nierkens S, Bierings MB, Versluijs AB, et al. Leukemia-free survival in myeloid leukemia, but not in lymphoid leukemia, is predicted by early CD4+ reconstitution following unrelated cord blood transplantation in children: a multicenter retrospective cohort analysis. Bone Marrow Transpl. 2016;51:1376–8.

    Article 
    CAS 

    Google Scholar
     

  • Clave E, Lisini D, Douay C, Giorgiani G, Busson M, Zecca M et al. Thymic function recovery after unrelated donor cord blood or T-cell depleted HLA-haploidentical stem cell transplantation correlates with leukemia relapse. Front Immunol. 2013;4. https://doi.org/10.3389/fimmu.2013.00054.

  • Maury S, Mary J, Rabian C, Schwarzinger M, Toubert A, Scieux C, et al. Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients. Br J Haematol. 2001;115:630–41.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tsamadou C, Gowdavally S, Platzbecker U, Sala E, Valerius T, Wagner-Drouet E, et al. Donor genetic determinant of thymopoiesis rs2204985 impacts clinical outcome after single HLA mismatched hematopoietic stem cell transplantation. Bone Marrow Transpl. 2022;57:1539–47.

    Article 
    CAS 

    Google Scholar
     

  • Anderson G, Cosway EJ, James KD, Ohigashi I, Takahama Y. Generation and repair of thymic epithelial cells. J Exp Med. 2024;221:e20230894.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Granadier D, Acenas D, Dudakov JA. Endogenous thymic regeneration: restoring T cell production following injury. Nat Rev Immunol. 2025. https://doi.org/10.1038/s41577-024-01119-0.

  • Wertheimer T, Velardi E, Tsai J, Cooper K, Xiao S, Kloss CC, et al. Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration. Sci Immunol. 2018;3:eaal2736.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vaidya HJ, Briones Leon A, Blackburn CC. FOXN1 in thymus organogenesis and development. Eur J Immunol. 2016;46:1826–37.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Žuklys S, Handel A, Zhanybekova S, Govani F, Keller M, Maio S, et al. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat Immunol. 2016;17:1206–15.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kinsella S, Evandy CA, Cooper K, Cardinale A, Iovino L, deRoos P et al. Damage-induced pyroptosis drives endogenous thymic regeneration via induction of Foxn1 by purinergic receptor activation. 2023. https://doi.org/10.1101/2023.01.19.524800.

  • Zhao J, Hu R, Lai KC, Zhang Z, Lai L. Recombinant FOXN1 fusion protein increases T cell generation in old mice. Front Immunol. 2024;15:1423488.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Song Y, Su M, Zhu J, Di W, Liu Y, Hu R, et al. FOXN1 recombinant protein enhances T-cell regeneration after hematopoietic stem cell transplantation in mice. Eur J Immunol. 2016;46:1518–28.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zook EC, Krishack PA, Zhang S, Zeleznik-Le NJ, Firulli AB, Witte PL, et al. Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood. 2011;118:5723–31.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bredenkamp N, Nowell CS, Blackburn CC. Regeneration of the aged thymus by a single transcription factor. Development. 2014;141:1627–37.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen L, Xiao S, Manley NR. Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood. 2009;113:567–74.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bosticardo M, Yamazaki Y, Cowan J, Giardino G, Corsino C, Scalia G, et al. Heterozygous FOXN1 variants cause low TRECs and severe T cell lymphopenia, revealing a crucial role of FOXN1 in supporting early thymopoiesis. Am J Hum Genet. 2019;105:549–61.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moses A, Bhalla P, Thompson A, Lai L, Coskun FS, Seroogy CM, et al. Comprehensive phenotypic analysis of diverse FOXN1 variants. J Allergy Clin Immunol. 2023;152:1273–1291.e15.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Larsen BM, Cowan JE, Wang Y, Tanaka Y, Zhao Y, Voisin B, et al. Identification of an intronic regulatory element necessary for tissue-specific expression of Foxn1 in thymic epithelial cells. J Immunol. 2019;203:686–95.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kadouri N, Givony T, Nevo S, Hey J, Ben Dor S, Damari G, et al. Transcriptional regulation of the thymus master regulator Foxn1. Sci Immunol. 2022;7:eabn8144.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rossignol J-F. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antivir Res. 2014;110:94–103.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rossignol J-F, Abu-Zekry M, Hussein A, Santoro MG. Effect of nitazoxanide for treatment of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial. Lancet. 2006;368:124–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rossignol JA, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis. 2001;184:103–6.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rossignol J, Ayoub A, Ayers MS. Treatment of diarrhea caused by Giardia intestinalis and Entamoeba histolytica or E. dispar: a randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis. 2001;184:381–4.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Anderson VR, Curran MP. Nitazoxanide: a review of its use in the treatment of gastrointestinal infections. Drugs. 2007;67:1947–67.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gilles HM, Hoffman PS. Treatment of intestinal parasitic infections: a review of nitazoxanide. Trends Parasitol. 2002;18:95–97.

    Article 
    PubMed 

    Google Scholar
     

  • Haffizulla J, Hartman A, Hoppers M, Resnick H, Samudrala S, Ginocchio C, et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 2014;14:609–18.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lü Z, Li X, Li K, Ripani P, Shi X, Xu F, et al. Nitazoxanide and related thiazolides induce cell death in cancer cells by targeting the 20S proteasome with novel binding modes. Biochem Pharm. 2022;197:114913.

    Article 
    PubMed 

    Google Scholar
     

  • Chen X, Shi C, He M, Xiong S, Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther. 2023;8:352.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020;21:421–38.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, et al. A selective inhibitor of eIF2α dephosphorylation protects cells from ER stress. Science. 2005;307:935–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wortel IMN, Van Der Meer LT, Kilberg MS, Van Leeuwen FN. Surviving stress: modulation of ATF4-mediated stress responses in normal and malignant cells. Trends Endocrinol Metab. 2017;28:794–806.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Neill G, Masson GR. A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response. Front Mol Neurosci. 2023;16:1112253.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu Q, Nicol SA, Suen AYW, Baldwin TA. Examination of thymic positive and negative selection by flow cytometry. J Vis Exp. 2012;68:4269.

  • Li J, Wachsmuth LP, Xiao S, Condie BG, Manley NR. Foxn1 overexpression promotes thymic epithelial progenitor cell proliferation and mTEC maintenance, but does not prevent thymic involution. Dev Camb Engl. 2023;150:dev200995.

    CAS 

    Google Scholar
     

  • Du Q, Huynh LK, Coskun F, Molina E, King MA, Raj P, et al. FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans. J Clin Invest. 2019;129:4724–38.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kousa AI, Jahn L, Zhao K, Flores AE, Acenas D, Lederer E, et al. Age-related epithelial defects limit thymic function and regeneration. Nat Immunol. 2024;25:1593–606.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Horie K, Namiki K, Kinoshita K, Miyauchi M, Ishikawa T, Hayama M, et al. Acute irradiation causes a long-term disturbance in the heterogeneity and gene expression profile of medullary thymic epithelial cells. Front Immunol. 2023;14:1186154.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bredenkamp N, Nowell CS, Blackburn CC. Regeneration of the aged thymus by a single transcription factor. Dev Camb Engl. 2014;141:1627–37.

    CAS 

    Google Scholar
     

  • Srinivasan J, Lancaster JN, Singarapu N, Hale LP, Ehrlich LIR, Richie ER. Age-related changes in thymic central tolerance. Front Immunol. 2021;12:676236.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Takaba H, Takayanagi H. The mechanisms of T cell selection in the thymus. Trends Immunol. 2017;38:805–16.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Elyahu Y, Monsonego A. Thymus involution sets the clock of the aging T-cell landscape: Implications for declined immunity and tissue repair. Ageing Res Rev. 2021;65:101231.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liang Z, Dong X, Zhang Z, Zhang Q, Zhao Y. Age-related thymic involution: mechanisms and functional impact. Aging Cell. 2022;21:e13671.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017;14:417–33.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang H, Li X, Liu J, Lin X, Pei L, Boyce BF, et al. Proteasome inhibition-enhanced fracture repair is associated with increased mesenchymal progenitor cells in mice. PloS One. 2022;17:e0263839.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang F, Attarilar S, Xie K, Han C, Qingyang Liang, Huang K, et al. Carfilzomib alleviated osteoporosis by targeting PSME1/2 to activate Wnt/β-catenin signaling. Mol Cell Endocrinol. 2022;540:111520.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Caron AZ, Haroun S, Leblanc É, Trensz F, Guindi C, Amrani A, et al. The proteasome inhibitor MG132 reduces immobilization-induced skeletal muscle atrophy in mice. BMC Musculoskelet Disord. 2011;12:185.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Padrissa-Altés S, Zaouali MA, Boncompagni E, Bonaccorsi-Riani E, Carbonell T, Bardag-Gorce F, et al. The use of a reversible proteasome inhibitor in a model of Reduced-Size Orthotopic Liver transplantation in rats. Exp Mol Pathol. 2012;93:99–110.

    Article 
    PubMed 

    Google Scholar
     

  • Al-Homsi AS, Feng Y, Duffner U, Al Malki MM, Goodyke A, Cole K, et al. Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Exp Hematol. 2016;44:771–7.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Magenau JM, Reddy P. Proteasome: target for acute and chronic GVHD?. Blood. 2014;124:1551–2.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sun K, Welniak LA, Panoskaltsis-Mortari A, O’Shaughnessy MJ, Liu H, Barao I, et al. Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proc Natl Acad Sci USA. 2004;101:8120–5.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nelson AJ, Clegg CH, Farr AG. In vitro positive selection and anergy induction of class II-restricted TCR transgenic thymocytes by a cortical thymic epithelial cell line. Int Immunol. 1998;10:1335–46.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • O’Neil R, Wei Q, Condie B. High efficiency transfection of thymic epithelial cell lines and primary thymic epithelial cells by Nucleofection. Nat Preced. 2011. https://doi.org/10.1038/npre.2011.6283.1.