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01-03-2017 | Original Research Paper

Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation

Authors: Alessio Cortelazzo, Claudio de Felice, Silvia Leoncini, Cinzia Signorini, Roberto Guerranti, Roberto Leoncini, Alessandro Armini, Luca Bini, Lucia Ciccoli, Joussef Hayek

Published in: Inflammation Research | Issue 3/2017

Abstract

Background

Mutations in the cyclin-dependent kinase-like 5 gene cause a clinical variant of Rett syndrome (CDKL5-RTT). A role for the acute-phase response (APR) is emerging in typical RTT caused by methyl-CpG-binding protein 2 gene mutations (MECP2-RTT). No information is, to date, available on the inflammatory protein response in CDKL5-RTT. We evaluated, for the first time, the APR protein response in CDKL5-RTT.

Methods

Protein patterns in albumin- and IgG-depleted plasma proteome from CDKL5-RTT patients were evaluated by two-dimensional gel electrophoresis/mass spectrometry. The resulting data were related to circulating cytokines and compared to healthy controls or MECP2-RTT patients. The effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) were evaluated.

Results

CDKL5-RTT mutations resulted in a subclinical attenuated inflammation, specifically characterized by an overexpression of the complement component C3 and CD5 antigen-like, both strictly related to the inflammatory response. Cytokine dysregulation featuring a bulk increase of anti-inflammatory cytokines, predominantly IL-10, could explain the unchanged erythrocyte sedimentation rate and atypical features of inflammation in CDKL5-RTT. Omega-3 PUFAs were able to counterbalance the pro-inflammatory status.

Conclusion

For the first time, we revealed a subclinical smouldering inflammation pattern in CDKL5-RTT consisting in the coexistence of an atypical APR coupled with a dysregulated cytokine response.

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Weaving LS, Christodoulou J, Williamson SL, Friend KL, McKenzie OL, Archer H, et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet. 2004;75(6):1079–93.CrossRefPubMedPubMedCentral

Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007;56(3):422–37.CrossRefPubMed

Hanefeld F. The clinical pattern of the Rett syndrome. Brain Dev. 1985;783:320–5.CrossRef

Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, et al. Key clinical features to identify girls with CDKL5 mutations. Brain. 2008;131(Pt 10):2647–61.CrossRefPubMed

Mangatt M, Wong K, Anderson B, Epstein A, Hodgetts S, Leonard H, et al. Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet J Rare Dis. 2016;11:39. doi:10.1186/s13023-016-0418-y.CrossRefPubMedPubMedCentral

Cortelazzo A, De Felice C, Guerranti R, Signorini C, Leoncini S, Pecorelli A, et al. Subclinical inflammatory status in Rett syndrome. Mediators Inflamm. 2014;2014:480980. doi:10.1155/2014/480980.CrossRefPubMedPubMedCentral

Cronk JC, Derecki NC, Ji E, Xu Y, Lampano AE, Smirnov I, et al. Methyl-CpG binding protein 2 regulates microglia and macrophage gene expression in response to inflammatory stimuli. Immunity. 2015;42(2):679–91.CrossRefPubMedPubMedCentral

Derecki NC, Privman E, Kipnis J. Rett syndrome and other autism spectrum disorders-brain diseases of immune malfunction? Mol Psychiatry. 2010;15(4):355–63.CrossRefPubMedPubMedCentral

O’Driscoll CM, Lima MP, Kaufmann WE, Bressler JP. Methyl CpG binding protein 2 deficiency enhances expression of inflammatory cytokines by sustaining NF-κB signaling in myeloid derived cells. J Neuroimmunol. 2015;283:23–9.CrossRefPubMed

10.

Leoncini S, De Felice C, Signorini C, Zollo G, Cortelazzo A, Durand T, et al. Cytokine dysregulation in MECP2- and CDKL5-related Rett syndrome: relationships with aberrant redox homeostasis, inflammation, and ω-3 PUFAs. Oxid Med Cell Longev. 2015;2015:421624. doi:10.1155/2015/421624.CrossRefPubMedPubMedCentral

11.

Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944–50.CrossRefPubMedPubMedCentral

12.

Neul JL, Fang P, Barrish J, Lane J, Caeg EB, Smith EO, et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008;70(16):1313–21.CrossRefPubMedPubMedCentral

13.

FitzGerald PM, Jankovic J, Percy AK. Rett syndrome and associated movement disorders. Mov Disord. 1990;3(5):195–202.CrossRef

14.

Görg A, Obermaier C, Boguth G, Harder A, Scheibe B, Wildgruber R, et al. The current state of two-dimensional electrophoresis with immobilized pH gradients. Electrophoresis. 2000;21(6):1037–53.CrossRefPubMed

15.

Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.CrossRefPubMed

16.

Mortz E, Krogh TN, Vorum H, Görg A. Improved silver staining protocols for high sensitivity protein identification using matrix-assisted laser desorption/ionization-time of flight analysis. Proteomics. 2001;1(11):1359–63.CrossRefPubMed

17.

Hellman U, Wernstedt C, Góñez J, Heldin CH. Improvement of an “In-Gel” digestion procedure for the micropreparation of internal protein fragments for amino acid sequencing. Anal Biochem. 1995;224(1):451–5.CrossRefPubMed

18.

Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells. Immunology. 2006;117(4):433–42.CrossRefPubMedPubMedCentral

19.

Hunt JM, Tuder R. Alpha 1 anti-trypsin: one protein, many functions. Curr Mol Med. 2012;12(7):827–35.CrossRefPubMed

20.

Lee KY, Feng PH, Ho SC, Chuang KJ, Chen TT, Su CL, et al. Inter-alpha-trypsin inhibitor heavy chain 4: a novel biomarker for environmental exposure to particulate air pollution in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015;10:831–41.PubMedPubMedCentral

21.

Cubedo J, Padró T, Badimon L. Coordinated proteomic signature changes in immune response and complement proteins in acute myocardial infarction: the implication of serum amyloid P-component. Int J Cardiol. 2013;168(6):5196–204.CrossRefPubMed

22.

García-Rodríguez S, Arias-Santiago S, Perandrés-López R, Orgaz-Molina J, Castellote L, Buendía-Eisman A, et al. Decreased plasma levels of clusterin in patients with psoriasis. Actas Dermosifiliogr. 2013;104(6):497–503.CrossRefPubMed

23.

Jennewein C, Tran N, Paulus P, Ellinghaus P, Eble JA, Zacharowski K. Novel aspects of fibrin(ogen) fragments during inflammation. Mol Med. 2011;17(5–6):568–73.PubMedPubMedCentral

24.

Seruga B, Zhang H, Bernstein LJ, Tannock IF. Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer. 2008;8(11):887–99.CrossRefPubMed

25.

De Felice C, Leoncini S, Signorini C, Cortelazzo A, Rovero P, Durand T. Rett syndrome: an autoimmune disease? Autoimmun Rev. 2016;15(4):411–6.CrossRefPubMed

26.

Terkeltaub R. Apolipoprotein a-I at the interface of vascular inflammation and arthritis. Arterioscler Thromb Vasc Biol. 2014;34(3):474–6.CrossRefPubMedPubMedCentral

27.

Jeon B, Kim HR, Kim H, Chung DK. In vitro and in vivo downregulation of C3 by lipoteichoic acid isolated from Lactobacillus plantarum K8 suppressed cytokine-mediated complement system activation. FEMS Microbiol Lett. 2016;363(14). doi:10.1093/femsle/fnw140.

28.

Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest. 2007;117(3):746–56.CrossRefPubMedPubMedCentral

29.

Sanjurjo L, Amézaga N, Vilaplana C, Cáceres N, Marzo E, Valeri M, et al. The scavenger protein apoptosis inhibitor of macrophages (AIM) potentiates the antimicrobial response against Mycobacterium tuberculosis by enhancing autophagy. PLoS ONE. 2013;8(11):e79670. doi:10.1371/journal.pone.0079670.CrossRefPubMedPubMedCentral

30.

Sanjurjo L, Amézaga N, Aran G, Naranjo-Gómez M, Arias L, Armengol C, et al. The human CD5L/AIM-CD36 axis: A novel autophagy inducer in macrophages that modulates inflammatory responses. Autophagy. 2015;11(3):487–502.CrossRefPubMedPubMedCentral

31.

Samygina VR, Sokolov AV, Bourenkov G, Petoukhov MV, Pulina MO, Zakharova ET, et al. Ceruloplasmin: macromolecular assemblies with iron-containing acute phase proteins. PLoS ONE. 2013;8(7):e67145. doi:10.1371/journal.pone.0067145.CrossRefPubMedPubMedCentral

32.

Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014;1843(11):2563–82.CrossRefPubMed

33.

Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, et al. Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2011;127(4):701–21.CrossRefPubMed

34.

De Felice C, Signorini C, Durand T, Ciccoli L, Leoncini S, D’Esposito M, et al. Partial rescue of Rett syndrome by ω-3 polyunsaturated fatty acids (PUFAs) oil. Genes Nutr. 2012;7(3):447–58.CrossRefPubMedPubMedCentral

35.

Signorini C, De Felice C, Leoncini S, Durand T, Galano JM, Cortelazzo A, et al. Altered erythrocyte membrane fatty acid profile in typical Rett syndrome: effects of omega-3 polyunsaturated fatty acid supplementation. Prostaglandins Leukot Essent Fatty Acids. 2014;91(5):183–93.CrossRefPubMed

36.

Ciccoli L, De Felice C, Paccagnini E, Leoncini S, Pecorelli A, Signorini C, et al. Morphological changes and oxidative damage in Rett syndrome erythrocytes. Biochim Biophys Acta. 2012;1820(4):511–20.CrossRefPubMed

37.

Cortelazzo A, De Felice C, Guerranti R, Leoncini R, Barducci A, Leoncini S, et al. Erythrocyte cytoskeletal-plasma membrane protein network in Rett syndrome: effects of ω-3 polyunsaturated fatty acids. Curr Proteomics. 2015;12(4):217–26.CrossRef

38.

De Felice C, Cortelazzo A, Signorini C, Guerranti R, Leoncini S, Pecorelli A, et al. Effects of ω-3 polyunsaturated fatty acids on plasma proteome in Rett syndrome. Mediators Inflamm. 2013;2013:723269. doi:10.1155/2013/723269.CrossRefPubMedPubMedCentral

Title: Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation
Authors: Alessio Cortelazzo
Claudio de Felice
Silvia Leoncini
Cinzia Signorini
Roberto Guerranti
Roberto Leoncini
Alessandro Armini
Luca Bini
Lucia Ciccoli
Joussef Hayek
Publication date: 01-03-2017
Publisher: Springer International Publishing
Published in: Inflammation Research / Issue 3/2017
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-016-1014-2

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Conclusion

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