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Multiple myeloma gammopathies

Light chain amyloidosis induced inflammatory changes in cardiomyocytes and adipose-derived mesenchymal stromal cells

Abstract

Light chain (AL) amyloidosis is a progressive, degenerative disease characterized by the misfolding and amyloid deposition of immunoglobulin light chain (LC). The amyloid deposits lead to organ failure and death. Our laboratory is specifically interested in cardiac involvement of AL amyloidosis. We have previously shown that the fibrillar aggregates of LC proteins can be cytotoxic and arrest the growth of human RFP-AC16 cardiomyocytes in vitro. We showed that adipose-derived mesenchymal stromal cells (AMSC) can rescue the cardiomyocytes from the fibril-induced growth arrest through contact-dependent mechanisms. In this study, we examined the transcriptome changes of human cardiomyocytes and AMSC in the presence of AL amyloid fibrils. The presence of fibrils causes a ‘priming’ immune response in AMSC associated with interferon associated genes. Exposure to AL fibrils induced changes in the pathways associated with immune response and extracellular matrix components in cardiomyocytes. We also observed upregulation of innate immune-associated transcripts (chemokines, cytokines, and complement), suggesting that amyloid fibrils initiate an innate immune response on these cells, possibly due to phenotypic transformation. This study corroborates and expands our previous studies and identifies potential new immunologic mechanisms of action for fibril toxicity on human cardiomyocytes and AMSC rescue effect on cardiomyocytes.

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Fig. 1: AMSC cultured with Wil fibrils shows an immune-based priming response.
Fig. 2: Principal component analysis of RFP-AC16 cultures shows differential clustering separation from COCX with AMSC with and without Wil fibrils.
Fig. 3: RFP-AC16 cultured with Wil Fibrils shows upregulation of immune-related genes.
Fig. 4: Addition of AMSC for AC16 COCX Wil show differential changes in immune and metabolic pathways.

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References

  1. Baden EM, Sikkink LA, Ramirez-Alvarado M. Light chain amyloidosis-current findings and future prospects. Curr Protein Pept Sci. 2009;10:500–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  2. Blancas-Mejía LM, Ramirez-Alvarado M. Systemic amyloidoses. Annu Rev Biochem. 2013;82:745–74.

    PubMed  PubMed Central  Google Scholar 

  3. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005;112:2047–60.

    PubMed  Google Scholar 

  4. Merlini G. CyBorD: stellar response rates in AL amyloidosis. Blood. 2012;119:4343–5.

    PubMed  CAS  Google Scholar 

  5. Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, et al. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012;119:4391–4.

    PubMed  PubMed Central  CAS  Google Scholar 

  6. Gertz MA. Immunoglobulin light chain amyloidosis: 2016 update on diagnosis, prognosis, and treatment. Am J Hematol. 2016;91:947–56.

    PubMed  CAS  Google Scholar 

  7. Trinkaus-Randall V, Walsh MT, Steeves S, Monis G, Connors LH, Skinner M. Cellular response of cardiac fibroblasts to amyloidogenic light chains. Am J Pathol. 2005;166:197–208.

    PubMed  PubMed Central  CAS  Google Scholar 

  8. Brenner DA, Jain M, Pimentel DR, Wang B, Connors LH, Skinner M, et al. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circulation Res. 2004;94:1008–10.

    PubMed  CAS  Google Scholar 

  9. Sikkink L, Ramirez-Alvarado M. Cytotoxicity of amyloidogenic immunoglobulin light chains in cell culture. Cell death Dis. 2010;1:e98.

    PubMed  PubMed Central  CAS  Google Scholar 

  10. Levinson RT, Olatoye OO, Randles EG, Howell KG, DiCostanzo AC, Ramirez-Alvarado M. Role of mutations in the cellular internalization of amyloidogenic light chains into cardiomyocytes. Sci Rep. 2013;3:1278.

    PubMed  PubMed Central  Google Scholar 

  11. McWilliams-Koeppen HP, Foster JS, Hackenbrack N, Ramirez-Alvarado M, Donohoe D, Williams A, et al. Light chain amyloid fibrils cause metabolic dysfunction in human cardiomyocytes. PLoS ONE. 2015;10:e0137716.

    PubMed  PubMed Central  Google Scholar 

  12. Lin Y, Marin-Argany M, Dick CJ, Redhage KR, Blancas-Mejia LM, Bulur P, et al. Mesenchymal stromal cells protect human cardiomyocytes from amyloid fibril damage. Cytotherapy. 2017;19:1426–37.

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Marin-Argany M, Lin Y, Misra P, Williams A, Wall JS, Howell KG, et al. Cell damage in light chain amyloidosis: fibril internalization, toxicity and cell-mediated seeding. J Biol Chem. 2016;291:19813–25.

    PubMed  PubMed Central  CAS  Google Scholar 

  14. Buxbaum JN. Animal models of human amyloidoses: are transgenic mice worth the time and trouble? FEBS Lett 2009;583:2663–73.

    PubMed  PubMed Central  CAS  Google Scholar 

  15. Davidson MM, Nesti C, Palenzuela L, Walker WF, Hernandez E, Protas L, et al. Novel cell lines derived from adult human ventricular cardiomyocytes. J Mol Cell Cardiol. 2005;39:133–47.

    PubMed  CAS  Google Scholar 

  16. Poshusta TL, Katoh N, Gertz MA, Dispenzieri A, Ramirez-Alvarado M. Thermal stability threshold for amyloid formation in light chain amyloidosis. Int J Mol Sci. 2013;14:22604–17.

    PubMed  PubMed Central  Google Scholar 

  17. Wall J, Schell M, Murphy C, Hrncic R, Stevens FJ, Solomon A. Thermodynamic instability of human λ6 light chains: correlation with fibrillogenicity. Biochemistry 1999;38:14101–8.

    PubMed  CAS  Google Scholar 

  18. Wall JS, Gupta V, Wilkerson M, Schell M, Loris R, Adams P, et al. Structural basis of light chain amyloidogenicity: comparison of the thermodynamic properties, fibrillogenic potential and tertiary structural features of four Vλ6 proteins. J Mol Recognit. 2004;17:323–31.

    PubMed  CAS  Google Scholar 

  19. Bernardo ME, Locatelli F, Fibbe WE. Mesenchymal stromal cells. Ann New Y Acad Sci. 2009;1176:101–17.

    CAS  Google Scholar 

  20. Blancas-Mejia LM, Misra P, Dick CJ, Marin-Argany M, Redhage KR, Cooper SA, et al. Assays for light chain amyloidosis formation and cytotoxicity. Protein Misfolding Dis Springer. 2019;1873:p. 123–53.

  21. Dudakovic A, Camilleri E, Riester SM, Lewallen EA, Kvasha S, Chen X, et al. High‐resolution molecular validation of self‐renewal and spontaneous differentiation in clinical‐grade adipose‐tissue derived human mesenchymal stem cells. J Cell Biochem. 2014;115:1816–28.

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45:D362–8.

  23. Metsalu T, Vilo J. ClustVis: a web tool for visualizing clustering of multivariate data using principal component analysis and heatmap. Nucleic acids Res. 2015;43(W1):W566–W70.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Lin Y, Hogan WJ. Clinical application of mesenchymal stem cells in the treatment and prevention of graft-versus-host disease. Adv Hematol. 2011;2011:17.

    Google Scholar 

  25. Hafer‐Macko CE, Dyck PJ, Koski CL. Complement activation in acquired and hereditary amyloid neuropathy. J Peripheral Nerv Syst. 2000;5:131–9.

    Google Scholar 

  26. Rodolico C, Mazzeo A, Toscano A, Pastura C, Maimone D, Musumeci O, et al. Amyloid myopathy presenting with rhabdomyolysis: evidence of complement activation. Neuromuscul Disord. 2006;16:514–7.

    PubMed  CAS  Google Scholar 

  27. Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch A, Gilbertson JA, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature. 2010;468:93.

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Matsuoka Y, Picciano M, Malester B, LaFrancois J, Zehr C, Daeschner JM, et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol. 2001;158:1345–54.

    PubMed  PubMed Central  CAS  Google Scholar 

  29. Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017;9:eaaf6295.

    PubMed  PubMed Central  Google Scholar 

  30. Stoltzner SE, Grenfell TJ, Mori C, Wisniewski KE, Wisniewski TM, Selkoe DJ, et al. Temporal accrual of complement proteins in amyloid plaques in Down’s syndrome with Alzheimer’s disease. Am J Pathol. 2000;156:489–99.

    PubMed  PubMed Central  CAS  Google Scholar 

  31. Eikelenboom P, Hack C, Kamphorst W, Rozemuller J. Distribution pattern and functional state of complement proteins and alpha 1-antichymotrypsin in cerebral beta/A4 deposits in Alzheimer’s disease. Res Immunol. 1992;143:617–20.

    PubMed  CAS  Google Scholar 

  32. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol. 2008;9:857.

    PubMed  PubMed Central  CAS  Google Scholar 

  33. Masters SL, O’Neill LA. Disease-associated amyloid and misfolded protein aggregates activate the inflammasome. Trends Mol Med. 2011;17:276–82.

    PubMed  CAS  Google Scholar 

  34. Diomede L, Romeo M, Rognoni P, Beeg M, Foray C, Ghibaudi E, et al. Cardiac light chain amyloidosis: the role of metal ions in oxidative stress and mitochondrial damage. Antioxid redox Signal. 2017;27:567–82.

    PubMed  PubMed Central  CAS  Google Scholar 

  35. Russo RC, Garcia CC, Teixeira MM, Amaral FA. The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases. Expert Rev Clin Immunol. 2014;10:593–619.

    PubMed  CAS  Google Scholar 

  36. Kruger P, Saffarzadeh M, Weber AN, Rieber N, Radsak M, von Bernuth H, et al. Neutrophils: between host defence, immune modulation, and tissue injury. PLoS Pathog. 2015;11:e1004651.

    PubMed  PubMed Central  Google Scholar 

  37. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13:159.

    PubMed  CAS  Google Scholar 

  38. Keeling J, Teng J, Herrera GA. AL-amyloidosis and light-chain deposition disease light chains induce divergent phenotypic transformations of human mesangial cells. Lab Investig. 2004;84:1322.

    PubMed  CAS  Google Scholar 

  39. Teng J, Russell WJ, Gu X, Cardelli J, Jones ML, Herrera GA. Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns. Lab Investig. 2004;84:440.

    PubMed  CAS  Google Scholar 

  40. Horwitz EM, Andreef M, Frassoni F. Mesenchymal stromal cells. Curr Opin Hematol. 2006;13:419–25.

    PubMed Central  Google Scholar 

  41. Duijvestein M, Wildenberg ME, Welling MM, Hennink S, Molendijk I, van Zuylen VL, et al. Pretreatment with interferon‐γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells. 2011;29:1549–58.

    PubMed  CAS  Google Scholar 

  42. Pessina A, Bonomi A, Coccè V, Invernici G, Navone S, Cavicchini L, et al. Mesenchymal stromal cells primed with paclitaxel provide a new approach for cancer therapy. PLoS ONE. 2011;6:e28321.

    PubMed  PubMed Central  CAS  Google Scholar 

  43. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz A-L, Iggo R. Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet. 2003;34:263.

    PubMed  CAS  Google Scholar 

  44. Salomon R, Staeheli P, Kochs G, Yen H-L, Franks J, Rehg JE, et al. Mx1 gene protects mice against the highly lethal human H5N1 influenza virus. Cell Cycle. 2007;6:2417–21.

    PubMed  CAS  Google Scholar 

  45. Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, et al. The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide. PloS one. 2010;5:e9505.

    PubMed  PubMed Central  Google Scholar 

  46. Fulop T, Witkowski JM, Bourgade K, Khalil A, Zerif E, Larbi A, et al. Can an infection hypothesis explain the beta amyloid hypothesis of Alzheimer’s disease? Frontiers in aging. Neuroscience. 2018;10:224.

    Google Scholar 

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Acknowledgements

We thank the staff of the Medical Genome Facility Expression Core for carrying out the RNAseq analysis and the staff of the Flow Cytometry Core for their assistance. We also thank Michael Bergman, Shawna Cooper, Christopher Parks, and Christopher Paradise for their contributions to this project. TLJ is a graduate student at Mayo Clinic Graduate School of Biomedical Sciences. This work is submitted in partial fulfillment of the requirement for the PhD program. This study was supported in part by NIH R01 GM 128253, the Mayo Foundation, and the generous support of amyloidosis patients and their families.

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TLJ, MRA and YL designed experiments, analyzed results, and wrote the manuscript. TLJ, KM, PM, CJD, LBM, KRR, AW, conducted experiments AvW analyzed data and wrote the manuscript JSW analyzed data and wrote the manuscript

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Correspondence to Yi Lin or Marina Ramirez-Alvarado.

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Jordan, T.L., Maar, K., Redhage, K.R. et al. Light chain amyloidosis induced inflammatory changes in cardiomyocytes and adipose-derived mesenchymal stromal cells. Leukemia 34, 1383–1393 (2020). https://doi.org/10.1038/s41375-019-0640-4

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