Department of Clinical Immunology

Błyszczuk

Research topic: Pathophysiology of myocarditis and inflammatory dilated cardiomyopathy
 
Research problem: Inflammation of cardiac tissue called myocarditis is an inflammatory disease of the myocardium caused by various infectious and non-infectious triggers. Myocarditis often resolves spontaneously, but some patients progress into dilated cardiomyopathy, a condition characterised by interstitial and perivascular fibrosis, tissue remodelling, ventricular dilatation and heart failure. It is known from mouse models as well as from clinical observations that autoimmune mechanisms are critically involved in the development and progression of myocarditis. The mechanisms controlling these pathogenic processes remain, however, obscure and treatment options rather limited. 
 
Aim and methodology: Aim of our research is to elucidate molecular and cellular mechanisms controlling development of cardiac inflammation and post-inflammatory fibrosis. Understanding these mechanisms will open new opportunities for treatment therapies for inflammatory heart disease patients. In our research, we are using mouse model of experimental autoimmune myocarditis. In this model, immunisation with cardiac antigen activates autoreactive heart-specific CD4+ T cells, which initiate flux of inflammatory cells into the heart causing myocarditis. Resolution of inflammation is followed by development of cardiac fibrosis and left ventricular dysfunction in most animals. In vivo studies are supplemented by in vitro and ex vivo approaches using cells (mainly cardiac fibroblasts, microvascular endothelial cells, resident and inflammatory myeloid cells) obtained from mouse and human hearts.
 
Projects:
   •   Interplay between angiotensin II, WNT, Rho kinase and TGF-β signalling pathways in cardiac fibrosis
   •  Molecular mechanism of cardiac fibroblast activation in myocarditis
   •  Pro-inflammatory and anti-inflammatory mechanisms of TNF-α signalling in myocarditis
   •  Exosomes in dysfunction of the coronary microvasculature
   •  Autophagy in myocarditis and in myocardial fibrosis
   •  Profibrotic response of cardiac microvascular endothelial cells
 
 

Pathophysiology of myocarditis and dilated cardiomyopathy

 

Group members:

 

Prof. dr Przemysław Błyszczuk (group leader)

 

 

 

dr Marcin Czepiel (post-doc)

 

 

 

dr Monika Stefańska (post-doc)

 

 

 

Edyta Działo (PhD student)

 

 

 

Karolina Tkacz (PhD student)

 

 

 

Filip Rolski (PhD student)

 

 

 

Magdalena Bielawska (PhD student)

 

 

 

Anna Dobosz (PhD student)

 

 

Julia Cięciwa (technical assistant)

 

Selected original publications:

    1. Rolski F, Tkacz K, Węglarczyk K, Kwiatkowski G, Pelczar P, Jaźwa-Kusior A, Bar A, Kuster GM, Chłopicki S, Siedlar M, Kania G, Błyszczuk P. (2023) TNF-α protects from exacerbated myocarditis and cardiac death by suppressing expansion of activated heart-reactive CD4+ T cells, Cardiovasc Res.  Oct 25 online ahead of print
    2. Czepiel M, Diviani D, Jaźwa-Kusior A, Tkacz K, Rolski F, Smolenski RT, Siedlar M, Eriksson U, Kania G, Błyszczuk P (2022) Angiotensin II receptor 1 controls profibrotic Wnt/β-catenin signalling in experimental autoimmune myocarditis Cardiovasc Res. Jan 29;118(2):573-584
    3. Działo E, Czepiel M, Tkacz K, Siedlar M, Kania G, Błyszczuk P. (2021) WNT/β-Catenin Signaling Promotes TGF-β-Mediated Activation of Human Cardiac Fibroblasts by Enhancing IL-11 Production Int J Mol Sci. Sep 17;22(18):10072
    4. Tkacz K, Rolski F, Czepiel M, Działo E, Siedlar M, Eriksson U, Kania G, Błyszczuk P. (2020) Haploinsufficient Rock1+/- and Rock2+/- mice are not protected from cardiac inflammation and postinflammatory fibrosis in experimental autoimmune myocarditis Cells Mar 12;9(3):700
    5. Zarak-Crnkovic M, Kania G, Jaźwa-Kusior A, Czepiel M, Wijnen WJ, Czyż J, Müller-Edenborn B, Vdovenko D, Lindner D, Gil-Cruz C, Bachmann M, Westermann D, Ludewig B, Distler O, Lüscher TF, Klingel K, Eriksson U, Błyszczuk P. (2019) Heart non-specific effector CD4+ T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis. Basic Res Cardiol. Dec 20;115(1):6
    6. Działo E, Rudnik M, Koning RI, Czepiel M, Tkacz K, Baj-Krzyworzeka M, Distler O, Siedlar M, Kania G, Błyszczuk P (2019) WNT3a and WNT5a transported by exosomes activate WNT signaling pathways in human cardiac fibroblasts Int J Mol Sci. Mar 21;20(6)
    7. Stellato M, Czepiel M, Distler O, Błyszczuk P, Kania G. (2019) Identification and isolation of cardiac fibroblasts from the adult mouse heart using two-color flow cytometry Front Cardiovasc Med. Aug 1;6:105
    8. Blyszczuk P, Müller-Edenborn B, Valenta T, Osto E, Stellato M, Behnke S, Glatz K, Basler K, Lüscher T, Distler O, Eriksson U, Kania G. (2017) TGF-β-dependent Wnt secretion controls myofibroblast formation and myocardial fibrosis progression in experimental autoimmune myocarditis Eur Heart J. May 7;38(18), 1413-1425
    9. Kania G, Siegert S, Behnke S, Prados-Rosales R, Casadevall A, Lüscher T, Luther S, Kopf M, Eriksson U, Blyszczuk P (2013) Activation of Toll-like receptor 2 in the presence of interferon-gamma signaling induce formation of regulatory nitric oxide-producing dendritic cells limiting T cell expansion in experimental autoimmune myocarditis, Circulation 127, 2285-94
    10. Blyszczuk P, Berthonneche C, Behnke S, Glönkler M, Moch H, Pedrazzini T, Lüscher TF, Eriksson U, Kania G. (2013) Nitric oxide synthase 2 is required for conversion of pro-fibrogenic inflammatory CD133+ progenitors into F4/80+ macrophages in experimental autoimmune myocarditis Cardiovasc Res. 97(2), 219-29
    11. Blyszczuk P, Behnke S, Lüscher TF, Eriksson U, Kania G. (2013) GM-CSF promotes inflammatory dendritic cell formation but does not contribute to disease progression in experimental autoimmune myocarditis BBA Mol. Cell Res. 1833(4), 934-44
    12. Kania G, Blyszczuk P, Stein S, Valaperti A, Germano D, Dirnhofer S, Hunziker L, Matter CM, Eriksson U. (2009) Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of TGF-β-mediated cardiac fibrosis in experimental autoimmune myocarditis. Circulation Res. 105(5), 462-70
    13. Blyszczuk P, Kania G, Dieterle T, Marty RR, Valaperti A, Berthonneche C, Pedrazzini T, Berger CT, Dirnhofer S, Matter CM, Penninger JM, Lüscher TF, Eriksson U. (2009) Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy. Circulation Res. 105(9), 912-20

Selected reviews:

    2. Rolski F, Błyszczuk P. (2020) Complexity of TNF-α signaling in heart disease J Clin Med. Oct 12;9(10)
    3. Błyszczuk P (2019) Myocarditis in humans and in experimental animal models Front Cardiovasc Med. May 16;6:64
    4. Działo E, Tkacz K, Błyszczuk P. (2018) Crosstalk between TGF-β and WNT signalling pathways during cardiac fibrogenesis Acta Bioch. Pol. 65(3), 341-349
    5. Kania G, Blyszczuk P, Müller-Edenborn B, Eriksson U. (2013) Novel therapeutic options in inflammatory cardiomyopathy Swiss Med Wkly. 143;13841
    6. Kania G, Blyszczuk P, Eriksson U. (2009) Mechanisms of cardiac fibrosis in inflammatory heart disease. Trends Cardiovasc Med. 19(8), 247-52
    7. Blyszczuk P, Valaperti A, Eriksson U. (2008) Future therapeutic strategies in inflammatory cardiomyopathy: insights from the experimental autoimmune myocarditis model Cardiovasc Hematol Disord Drug Targets 8(4), 313-21

 

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