Mechanistic and therapeutic studies in cardiac inflammation
(2024) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Cardiovascular disease (CVD) is the leading cause of death globally. Inflammatory cardiomyopathies can be life-threatening, and the underlying mechanisms are not fully understood. This thesis aimed to investigate the underlying mechanisms driving the pathogenesis of myocarditis and septic cardiomyopathy, and to explore potential treatment strategies. In particular, we focused on the pro-inflammatory neutrophil mediator S100A8/A9 and on IL-1RAP, a common accessory protein required for IL-1ɑ, IL-1β, IL-33 and IL-36 receptor signaling.
To study the role of S100A8/A9 in sepsis-induced myocardial dysfunction (SIMD), we measured plasma S100A8/A9 levels in patients with severe sepsis. S100A8/A9 was significantly higher in patients with... (More) - Cardiovascular disease (CVD) is the leading cause of death globally. Inflammatory cardiomyopathies can be life-threatening, and the underlying mechanisms are not fully understood. This thesis aimed to investigate the underlying mechanisms driving the pathogenesis of myocarditis and septic cardiomyopathy, and to explore potential treatment strategies. In particular, we focused on the pro-inflammatory neutrophil mediator S100A8/A9 and on IL-1RAP, a common accessory protein required for IL-1ɑ, IL-1β, IL-33 and IL-36 receptor signaling.
To study the role of S100A8/A9 in sepsis-induced myocardial dysfunction (SIMD), we measured plasma S100A8/A9 levels in patients with severe sepsis. S100A8/A9 was significantly higher in patients with left ventricular dysfunction compared with patients with normal cardiac function. Further, S100A8/A9 blockade with a small-molecule inhibitor improved cardiac dysfunction and reduced systemic and cardiac inflammation in a mouse model of endotoxemia. S1009 knockout mice were similarly protected, suggesting a direct pathogenic role of S100A8/A9 in SIMD. Lastly, we found that S100A8/A9 inhibition was faster and more effective than glucocorticoids against SIMD development in endotoxemia.
In a mouse model of autoimmune myocarditis, we investigated the role of neutrophil-derived S100A8/A9 in the pathogenesis of the disease, by depleting neutrophils and blocking S100A8/A9. Neutrophil depletion prevented cardiac dysfunction, confirming their pathogenic role. S100A8/A9 blockade limited the recruitment of innate immune phagocytes into the myocardium, reduced myocardial apoptosis, and improved cardiac function. By single-cell RNA sequencing analysis, we revealed for the first time five distinct neutrophil subpopulations infiltrating the heart in myocarditis. Mechanistically, S100A8/A9 blockade polarized the infiltrating neutrophils from an inflammatory phenotype into a predominantly immunomodulatory one, preventing excessive inflammatory activation in the myocardium.
Lastly, we tested treatment with an anti-IL-1RAP monoclonal antibody, blocking IL-1ɑ, IL-1β, IL-33 and IL-36 signaling, in two murine models of myocarditis. The anti-IL-1RAP antibody reduced the severity of both viral and autoimmune myocarditis. The treatment prevented long-term left ventricular dysfunction in mice with autoimmune myocarditis compared with isotype controls and IL-1β blockade alone. Importantly, IL-1RAP blockade potently reduced myeloid and T cell infiltration into the myocardium but did not hinder viral clearance.
We demonstrate a direct pathogenic role for S100A8/A9 in SIMD and autoimmune myocarditis, and the involvement of IL-1RAP-mediated signaling in the pathogenesis of both autoimmune and viral myocarditis. Our findings promote S100A8/A9 blockade as a potential future treatment for severe sepsis patients with SIMD. Both small-molecule S100A8/A9 blockade and antibody-mediated IL-1RAP inhibition are promising immunomodulatory therapies that warrant further development for treatment of patients with acute myocarditis.
(Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/b5c78886-8f5d-4f10-97db-cab4a1499190
- author
- Jakobsson, Gabriel LU
- supervisor
- opponent
-
- Professor, M.Pharm, PhD, FAHA Nagareddy, Prabhakara R, Department of Internal Medicine, Cardiovascular section, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- organization
- publishing date
- 2024
- type
- Thesis
- publication status
- published
- subject
- keywords
- inflammatory cardiomyopathy, sepsis, Sepsis-induced myocardial dysfunction, myocarditis, neutrophils, inflammation, S100A8/A9, IL-1 receptor accessory protein, immunomodulation
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2024:99
- pages
- 79 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Agardh föreläsningssal, CRC, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö
- defense date
- 2024-09-13 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-595-4
- language
- English
- LU publication?
- yes
- id
- b5c78886-8f5d-4f10-97db-cab4a1499190
- date added to LUP
- 2024-08-21 11:05:34
- date last changed
- 2024-08-27 12:03:32
@phdthesis{b5c78886-8f5d-4f10-97db-cab4a1499190, abstract = {{Cardiovascular disease (CVD) is the leading cause of death globally. Inflammatory cardiomyopathies can be life-threatening, and the underlying mechanisms are not fully understood. This thesis aimed to investigate the underlying mechanisms driving the pathogenesis of myocarditis and septic cardiomyopathy, and to explore potential treatment strategies. In particular, we focused on the pro-inflammatory neutrophil mediator S100A8/A9 and on IL-1RAP, a common accessory protein required for IL-1ɑ, IL-1β, IL-33 and IL-36 receptor signaling.<br/><br/>To study the role of S100A8/A9 in sepsis-induced myocardial dysfunction (SIMD), we measured plasma S100A8/A9 levels in patients with severe sepsis. S100A8/A9 was significantly higher in patients with left ventricular dysfunction compared with patients with normal cardiac function. Further, S100A8/A9 blockade with a small-molecule inhibitor improved cardiac dysfunction and reduced systemic and cardiac inflammation in a mouse model of endotoxemia. S1009 knockout mice were similarly protected, suggesting a direct pathogenic role of S100A8/A9 in SIMD. Lastly, we found that S100A8/A9 inhibition was faster and more effective than glucocorticoids against SIMD development in endotoxemia.<br/><br/>In a mouse model of autoimmune myocarditis, we investigated the role of neutrophil-derived S100A8/A9 in the pathogenesis of the disease, by depleting neutrophils and blocking S100A8/A9. Neutrophil depletion prevented cardiac dysfunction, confirming their pathogenic role. S100A8/A9 blockade limited the recruitment of innate immune phagocytes into the myocardium, reduced myocardial apoptosis, and improved cardiac function. By single-cell RNA sequencing analysis, we revealed for the first time five distinct neutrophil subpopulations infiltrating the heart in myocarditis. Mechanistically, S100A8/A9 blockade polarized the infiltrating neutrophils from an inflammatory phenotype into a predominantly immunomodulatory one, preventing excessive inflammatory activation in the myocardium.<br/><br/>Lastly, we tested treatment with an anti-IL-1RAP monoclonal antibody, blocking IL-1ɑ, IL-1β, IL-33 and IL-36 signaling, in two murine models of myocarditis. The anti-IL-1RAP antibody reduced the severity of both viral and autoimmune myocarditis. The treatment prevented long-term left ventricular dysfunction in mice with autoimmune myocarditis compared with isotype controls and IL-1β blockade alone. Importantly, IL-1RAP blockade potently reduced myeloid and T cell infiltration into the myocardium but did not hinder viral clearance.<br/><br/>We demonstrate a direct pathogenic role for S100A8/A9 in SIMD and autoimmune myocarditis, and the involvement of IL-1RAP-mediated signaling in the pathogenesis of both autoimmune and viral myocarditis. Our findings promote S100A8/A9 blockade as a potential future treatment for severe sepsis patients with SIMD. Both small-molecule S100A8/A9 blockade and antibody-mediated IL-1RAP inhibition are promising immunomodulatory therapies that warrant further development for treatment of patients with acute myocarditis.<br/>}}, author = {{Jakobsson, Gabriel}}, isbn = {{978-91-8021-595-4}}, issn = {{1652-8220}}, keywords = {{inflammatory cardiomyopathy; sepsis; Sepsis-induced myocardial dysfunction; myocarditis; neutrophils; inflammation; S100A8/A9; IL-1 receptor accessory protein; immunomodulation}}, language = {{eng}}, number = {{2024:99}}, publisher = {{Lund University, Faculty of Medicine}}, school = {{Lund University}}, series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}}, title = {{Mechanistic and therapeutic studies in cardiac inflammation}}, year = {{2024}}, }