Abstract
Myocarditis is an inflammatory disease of the heart muscle most commonly caused by viral infection and often maintained by autoimmunity. Virus-induced tissue damage triggers chemokine production and, subsequently, immune cell infiltration with pro-inflammatory and pro-fibrotic cytokine production follows. In patients, the overall inflammatory burden determines the disease outcome. Following the aim to define specific molecules that drive both immunopathology and/or autoimmunity in inflammatory heart disease, here we report on increased expression of colony stimulating factor 1 (CSF-1) in patients with myocarditis. CSF-1 controls monocytes originating from hematopoietic stem cells and subsequent progenitor stages. Both, monocytes and macrophages are centrally involved in mediating tissue damage and fibrotic scarring in the heart. CSF-1 influences monocytes via engagement of CSF-1 receptor, and it is also produced by cells of the mononuclear phagocyte system themselves. Based on this, we sought to modulate the virus-triggered inflammatory response in an experimental model of Coxsackievirus B3-induced myocarditis by silencing the CSF-1 axis in myeloid cells using nanoparticle-encapsulated siRNA. siCSF-1 inverted virus-mediated immunopathology as reflected by lower troponin T levels, a reduction of accumulating myeloid cells in heart tissue and improved cardiac function. Importantly, pathogen control was maintained and the virus was efficiently cleared from heart tissue. Since viral heart disease triggers heart-directed autoimmunity, in a second approach we investigated the influence of CSF-1 upon manifestation of heart tissue inflammation during experimental autoimmune myocarditis (EAM). EAM was induced in Balb/c mice by immunization with a myocarditogenic myosin-heavy chain-derived peptide dissolved in complete Freund's adjuvant. siCSF-1 treatment initiated upon established disease inhibited monocyte infiltration into heart tissue and this suppressed cardiac injury as reflected by diminished cardiac fibrosis and improved cardiac function at later states. Mechanistically, we found that suppression of CSF-1 production arrested both differentiation and maturation of monocytes and their precursors in the bone marrow. In conclusion, during viral and autoimmune myocarditis silencing of the myeloid CSF-1 axis by nanoparticle-encapsulated siRNA is beneficial for preventing inflammatory tissue damage in the heart and preserving cardiac function without compromising innate immunity's critical defense mechanisms.
Highlights
Myocarditis and its sequela, dilated cardiomyopathy, are leading causes of heart failure and sudden death in young adults [1]
Immunohistochemical stain of heart tissue from patients with myocarditis revealed Colony Stimulating Factor 1 (CSF-1) expressing cells only within inflammatory foci, with a strong focus on mononuclear immune cells (Figure 2A). These data argued toward a significant contribution of monocytes/macrophages to the cardiac CSF-1 expression, which we found in patients with inflammatory heart disease
In immune-genetically predisposed individuals there is an adverse scenario where pathogen-induced immune response activation subsequently induces overwhelming inflammatory cytokine response and detrimental immunopathology or autoimmune processes, both leading to cardiac remodeling and fibrotic scarring
Summary
Myocarditis and its sequela, dilated cardiomyopathy, are leading causes of heart failure and sudden death in young adults [1]. Severe virus-induced inflammation can result in a subsequent loss of self-tolerance against cardiac proteins, which contributes to additive auto-destructive activity of infiltrating cells and exaggerates heart tissue damage [9, 10]. Cardiac myosin is such a crucial autoantigen in both human and murine virus-induced myocarditis [9]. Administration of cardiac myosin or its pathogenic epitope in combination with an adjuvant induces experimental autoimmune myocarditis (EAM) in mice, a model that mimics certain aspects of myocarditis and heart failure in humans [11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
