Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis

Nature Medicine

Volumn 23, Issue 5, 2017, Pages 590-600

  Romani, Luigina ^a   Oikonomou, Vasilis ^a   Moretti, Silvia ^a   Iannitti, Rossana G ^a   D'Adamo, Maria Cristina ^b   Villella, Valeria R ^c   Pariano, Marilena ^a   Sforna, Luigi ^a   Borghi, Monica ^a   Bellet, Marina M ^a   Fallarino, Francesca ^a   Pallotta, Maria Teresa ^a   Servillo, Giuseppe ^a   Ferrari, Eleonora ^c   Puccetti, Paolo ^a   Kroemer, Guido ^d,e,f,g   Pessia, Mauro ^a,b   Maiuri, Luigi ^c,h   Goldstein, Allan L ⁱ   Garaci, Enrico ^j  

^a UNIVERSITY OF PERUGIA   (Italy)

^b UNIVERSITY OF MALTA   (Malta)

^c SAN RAFFAELE HOSPITAL   (Italy)

^d CENTRE DE RECHERCHE DES CORDELIERS   (France)

^e INSTITUT GUSTAVE ROUSSY   (France)

^f HÔPITAL EUROPÉEN GEORGES POMPIDOU   (France)

^g KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^h UNIVERSITY OF EASTERN PIEDMONT   (Italy)

ⁱ GEORGE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE AND HEALTH SCIENCES   (United States)

^j Faculty of Architecture and Industrial Design   (Italy)

more..

Author keywords

[No Author keywords available]

Indexed keywords

CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; THYMOSIN ALPHA1; CHLORIDE CHANNEL; CLCA1 PROTEIN, MOUSE; CYTOKINE; IDO1 PROTEIN, MOUSE; IMMUNOLOGICAL ADJUVANT; INDOLEAMINE 2,3 DIOXYGENASE; THYMOSIN; UBIQUITIN THIOLESTERASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; CYSTIC FIBROSIS; FEMALE; MOUSE; NONHUMAN; PERMEABILITY; PRIORITY JOURNAL; SYMPTOMATOLOGY; ANALOGS AND DERIVATIVES; ANIMAL; AUTOPHAGY; CELL LINE; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MOUSE; CYTOLOGY; DISEASE MODEL; DRUG EFFECTS; EPITHELIUM CELL; FLUORESCENT ANTIBODY TECHNIQUE; GENETICS; HUMAN; IMMUNOHISTOCHEMISTRY; IMMUNOLOGY; IMMUNOPRECIPITATION; INFLAMMATION; METABOLISM; PATCH CLAMP TECHNIQUE; PROTEIN STABILITY; RAW 264.7 CELL LINE; RESPIRATORY MUCOSA; UBIQUITINATION; WESTERN BLOTTING;

ADJUVANTS, IMMUNOLOGIC; ANIMALS; AUTOPHAGY; BLOTTING, WESTERN; CELL LINE; CHLORIDE CHANNELS; CYSTIC FIBROSIS; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CYTOKINES; DISEASE MODELS, ANIMAL; EPITHELIAL CELLS; FLUORESCENT ANTIBODY TECHNIQUE; HUMANS; IMMUNOHISTOCHEMISTRY; IMMUNOPRECIPITATION; INDOLEAMINE-PYRROLE 2,3,-DIOXYGENASE; INFLAMMATION; MICE; MICE, INBRED CFTR; PATCH-CLAMP TECHNIQUES; PROTEIN STABILITY; RAW 264.7 CELLS; RESPIRATORY MUCOSA; THYMOSIN; UBIQUITIN THIOLESTERASE; UBIQUITINATION;

EID: 85017218584     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.4305     Document Type: Article

References (69)

1. Rowe, S. M., Miller, S. & Sorscher, E. J. Cystic fibrosis. N. Engl. J. Med. 352, 1992-2001 (2005).
2. Lukacs, G. L. & Verkman, A. S. CFTR: folding, misfolding and correcting the F508 conformational defect. Trends Mol. Med. 18, 81-91 (2012).
3. Okiyoneda, T. et al. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science 329, 805-810 (2010).
4. Pedemonte, N. et al. Small-molecule correctors of defective F508-CFTR cellular processing identified by high-throughput screening. J. Clin. Invest. 115, 2564-2571 (2005).
5. Galietta, L. J. Managing the underlying cause of cystic fibrosis: a future role for potentiators and correctors. Paediatr. Drugs 15, 393-402 (2013).
6. Wainwright, C. E., Elborn, J. S. & Ramsey, B. W. Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N. Engl. J. Med. 373, 1783-1784 (2015).
7. Quon, B. S. & Rowe, S. M. New and emerging targeted therapies for cystic fibrosis. Br. Med. J. 352, i859 (2016).
8. Hegde, R. N. et al. Unravelling druggable signalling networks that control F508del-CFTR proteostasis. eLife 4, e10365 (2015).
9. Tosco, A. et al. A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR. Cell Death Differ. 23, 1380-1393 (2016).
10. Villella, V. R. et al. Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator. Cell Death Differ. 20, 1101-1115 (2013).
11. Cantin, A. M., Hartl, D., Konstan, M. W. & Chmiel, J. F. Inflammation in cystic fibrosis lung disease: pathogenesis and therapy. J. Cyst. Fibros. 14, 419-430 (2015).
12. Rubin, B. K. Cystic fibrosis: myths, mistakes, and dogma. Paediatr. Respir. Rev. 15, 113-116 (2014).
13. Cohen, T. S. & Prince, A. Cystic fibrosis: a mucosal immunodeficiency syndrome. Nat. Med. 18, 509-519 (2012).
14. Hoffman, L. R. & Ramsey, B. W. Cystic fibrosis therapeutics: the road ahead. Chest 143, 207-213 (2013).
15. de Benedictis, F. M. & Bush, A. Corticosteroids in respiratory diseases in children. Am. J. Respir. Crit. Care Med. 185, 12-23 (2012).
16. Devor, D. C. & Schultz, B. D. Ibuprofen inhibits cystic fibrosis transmembrane conductance regulator-mediated Cl-secretion. J. Clin. Invest. 102, 679-687 (1998).
17. Goldstein, A. L. & Goldstein, A. L. From lab to bedside: emerging clinical applications of thymosin 1. Expert Opin. Biol. Ther. 9, 593-608 (2009).
18. Romani, L. et al. Thymosin 1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance. Blood 108, 2265-2274 (2006).
19. Mandaliti, W. et al. New studies about the insertion mechanism of thymosin 1 in negative regions of model membranes as starting point of the bioactivity. Amino Acids 48, 1231-1239 (2016).
20. Tuthill, C. V. & King, R. S. Thymosin 1-a peptide immune modulator with a broad range of clinical applications. Clin. Exp. Pharmacol. 3, 133 (2013).
21. Puccetti, P. & Grohmann, U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-B activation. Nat. Rev. Immunol. 7, 817-823 (2007).
22. Iannitti, R. G. et al. Th17/Treg imbalance in murine cystic fibrosis is linked to indoleamine 2, 3-dioxygenase deficiency but corrected by kynurenines. Am. J. Respir. Crit. Care Med. 187, 609-620 (2013).
23. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5, 190-198 (2004).
24. Bruscia, E. et al. Isolation of CF cell lines corrected at F508-CFTR locus by SFHR-mediated targeting. Gene Ther. 9, 683-685 (2002).
25. King, J., Brunel, S. F. & Warris, A. Aspergillus infections in cystic fibrosis. J. Infect. 72 (Suppl. 1), S50-S55 (2016).
26. King, R. S. & Tuthill, C. Evaluation of thymosin 1 in nonclinical models of the immune-suppressing indications melanoma and sepsis. Expert Opin. Biol. Ther. 15 (Suppl. 1), S41-S49 (2015).
27. Ancell, C. D., Phipps, J. & Young, L. Thymosin-1. Am. J. Health Syst. Pharm. 58, 879-885; quiz 886-878 (2001).
28. Iannitti, R. G. et al. IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis. Nat. Commun. 7, 10791 (2016).
29. Snouwaert, J. N. et al. An animal model for cystic fibrosis made by gene targeting. Science 257, 1083-1088 (1992).
30. Stoltz, D. A., Meyerholz, D. K. & Welsh, M. J. Origins of cystic fibrosis lung disease. N. Engl. J. Med. 372, 351-362 (2015).
31. McGaha, T. L. IDO-GCN2 and autophagy in inflammation. Oncotarget 6, 21771-21772 (2015).
32. Luciani, A. et al. Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat. Cell Biol. 12, 863-875 (2010).
33. Pica, F. et al. Serum thymosin 1 levels in patients with chronic inflammatory autoimmune diseases. Clin. Exp. Immunol. 186, 39-45 (2016).
34. Denning, G. M. et al. Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 358, 761-764 (1992).
35. Bomberger, J. M., Barnaby, R. L. & Stanton, B. A. The deubiquitinating enzyme USP10 regulates the post-endocytic sorting of cystic fibrosis transmembrane conductance regulator in airway epithelial cells. J. Biol. Chem. 284, 18778-18789 (2009).
36. Gentzsch, M. et al. Endocytic trafficking routes of wild type and F508 cystic fibrosis transmembrane conductance regulator. Mol. Biol. Cell 15, 2684-2696 (2004).
37. Sarandeses, C. S., Covelo, G., Díaz-Jullien, C. & Freire, M. Prothymosin is processed to thymosin 1 and thymosin l11 by a lysosomal asparaginyl endopeptidase. J. Biol. Chem. 278, 13286-13293 (2003).
38. Heard, A., Thompson, J., Carver, J., Bakey, M. & Wang, X. R. Targeting molecular chaperones for the treatment of cystic fibrosis: is it a viable approach? Curr. Drug Targets 16, 958-964 (2015).
39. Millard, S. M. & Wood, S. A. Riding the DUBway: regulation of protein trafficking by deubiquitylating enzymes. J. Cell Biol. 173, 463-468 (2006).
40. Taillebourg, E. et al. The deubiquitinating enzyme USP36 controls selective autophagy activation by ubiquitinated proteins. Autophagy 8, 767-779 (2012).
41. Hassink, G. C. et al. The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates. EMBO Rep. 10, 755-761 (2009).
42. Kucera, A. et al. Spatiotemporal resolution of Rab9 and CI-MPR dynamics in the endocytic pathway. Traffic 17, 211-229 (2016).
43. Lamark, T. & Johansen, T. Autophagy: links with the proteasome. Curr. Opin. Cell Biol. 22, 192-198 (2010).
44. Zhang, L. et al. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. PLoS Biol. 7, e1000155 (2009).
45. Van Goor, F. et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc. Natl. Acad. Sci. USA 108, 18843-18848 (2011).
46. Yu, H. et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J. Cyst. Fibros. 11, 237-245 (2012).
47. Van Goor, F., Yu, H., Burton, B. & Hoffman, B. J. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J. Cyst. Fibros. 13, 29-36 (2014).
48. Caputo, A. et al. TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science 322, 590-594 (2008).
49. Sala-Rabanal, M., Yurtsever, Z., Nichols, C. G. & Brett, T. J. Secreted CLCA1 modulates TMEM16A to activate Ca2+-dependent chloride currents in human cells. eLife 4 http://dx. doi. org/10. 7554/eLife. 05875 (2015).
50. Dalakas, M. C., Engel, W. K., McClure, J. E., Goldstein, A. L. & Askanas, V. Immunocytochemical localization of thymosin-1 in thymic epithelial cells of normal and myasthenia gravis patients and in thymic cultures. J. Neurol. Sci. 50, 239-247 (1981).
51. Collawn, J. F. & Matalon, S. CFTR and lung homeostasis. Am. J. Physiol. Lung Cell. Mol. Physiol. 307, L917-L923 (2014).
52. Yuk, J. M. & Jo, E. K. Crosstalk between autophagy and inflammasomes. Mol. Cells 36, 393-399 (2013).
53. Soares, M. P., Gozzelino, R. & Weis, S. Tissue damage control in disease tolerance. Trends Immunol. 35, 483-494 (2014).
54. Darrah, R. J. et al. Early pulmonary disease manifestations in cystic fibrosis mice. J. Cyst. Fibros. 15, 736-744 (2016).
55. van der Doef, H. P. et al. Association of the CLCA1 p. S357N variant with meconium ileus in European patients with cystic fibrosis. J. Pediatr. Gastroenterol. Nutr. 50, 347-349 (2010).
56. Young, F. D. et al. Amelioration of cystic fibrosis intestinal mucous disease in mice by restoration of mCLCA3. Gastroenterology 133, 1928-1937 (2007).
57. Clarke, L. L. et al. Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in Cftr/ mice. Proc. Natl. Acad. Sci. USA 91, 479-483 (1994).
58. Boyle, M. P. et al. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a Phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir. Med. 2, 527-538 (2014).
59. Fajac, I. & De Boeck, K. New horizons for cystic fibrosis treatment. Pharmacol. Ther. 170, 205-211 (2017).
60. Pilewski, J. M., Donaldson, S. H., Cooke, J. & Lekstrom-Himes, J. Phase 2 studies reveal additive effects of VX-661, an investigational CFTR corrector, and ivacaftor, a CFTR potentiator, in patients who carry the F508-CFTR mutation. Pediatr. Pulmonol. 49, 157-159 (2014).
61. van Doorninck, J. H. et al. A mouse model for the cystic fibrosis F508 mutation. EMBO J. 14, 4403-4411 (1995).
62. De Stefano, D. et al. Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation. Autophagy 10, 2053-2074 (2014).
63. de Luca, A. et al. Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO. Cell. Mol. Immunol. 7, 459-470 (2010).
64. Loffing, J., Moyer, B. D., McCoy, D. & Stanton, B. A. Exocytosis is not involved in activation of Cl secretion via CFTR in Calu-3 airway epithelial cells. Am. J. Physiol. 275, C913-C920 (1998).
65. Pallotta, M. T. et al. Indoleamine 2, 3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat. Immunol. 12, 870-878 (2011).
66. Schägger, H. Tricine-SDS-PAGE. Nat. Protoc. 1, 16-22 (2006).
67. Sowa, M. E., Bennett, E. J., Gygi, S. P. & Harper, J. W. Defining the human deubiquitinating enzyme interaction landscape. Cell 138, 389-403 (2009).
68. De Luca, A. et al. CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease. J. Clin. Invest. 122, 1816-1831 (2012).
69. Munkonge, F. et al. Measurement of halide efflux from cultured and primary airway epithelial cells using fluorescence indicators. J. Cyst. Fibros. 3 (Suppl. 2), 171-176 (2004).