Periodic Reporting for period 1 - REMAKIN (REstoring myocardial repair capacity via the modulation of MAcrophage-mediated cytoKINe secretion.)
Periodo di rendicontazione: 2019-08-01 al 2021-07-31
Type-2 diabetes (T2D) is a chronic condition generating enormous healthcare costs. To make things worse, prevalence of T2D is increasing at an alarming rate worldwide.
T2D is caused by peripheral insulin resistance (IR) and is associated with cardiovascular diseases and myocardial infarction (MI) in particular.
Myocardial infarction triggers a sterile, innate inflammatory response essential for successful tissue repair and remodelling. Macrophages are innate inflammatory cells that play a strategic role by tightly controlling inflammation and orchestrating the remodelling of the infarcted heart through the secretion of immunomodulatory cytokines and by clearing the injured cardiac tissue from dead cells through a process called efferocytosis.
In chronic inflammatory diseases such as Type-2 Diabetes (T2D), the immunomodulatory role of macrophages is impaired, leading to unchecked, chronic inflammation driving adverse tissue remodelling and the development of heart failure. However, the molecular mechanisms underlying the immunomodulatory function of macrophages and how they are affected during insulin resistance remains completely unknown.
The objectives of the REMAKIN project are designed to improve our understanding on two critical points: how macrophages modulate inflammation in the infarcted heart and how T2D affects it.
T2D is caused by peripheral insulin resistance (IR) and is associated with cardiovascular diseases and myocardial infarction (MI) in particular.
Myocardial infarction triggers a sterile, innate inflammatory response essential for successful tissue repair and remodelling. Macrophages are innate inflammatory cells that play a strategic role by tightly controlling inflammation and orchestrating the remodelling of the infarcted heart through the secretion of immunomodulatory cytokines and by clearing the injured cardiac tissue from dead cells through a process called efferocytosis.
In chronic inflammatory diseases such as Type-2 Diabetes (T2D), the immunomodulatory role of macrophages is impaired, leading to unchecked, chronic inflammation driving adverse tissue remodelling and the development of heart failure. However, the molecular mechanisms underlying the immunomodulatory function of macrophages and how they are affected during insulin resistance remains completely unknown.
The objectives of the REMAKIN project are designed to improve our understanding on two critical points: how macrophages modulate inflammation in the infarcted heart and how T2D affects it.
The main achievements of the REMAKIN project are:
• Identifying efferocytosis as a trigger for controlled cytokine secretion mechanism.
• Identifying efferocytosis-stimulated cytokine secretion as a key mechanism for the homeostasis of protective cardiac resident macrophage populations.
• Identifying efferocytosis-stimulated cytokine secretion as a key mechanism to maintain cardiac homeostasis at steady state and myocardial remodelling after infarction.
• Identifying that insulin resistance, the pathophysiological mechanism leading to T2D impairs efferocytosis-stimulated cytokine secretion and leads to adverse remodelling of the infarcted myocardium.
A better understanding of the molecular mechanisms underlying macrophages’ immunomodulatory role will foster novel and efficient therapeutic strategies to restore this functionality in macrophages from diabetic patients. By restoring control over inflammation, such therapies would tremendously improve incidence of cardiovascular events and survival in patients suffering from T2D by improving post-MI remodelling.
This work will be presented to national and international conferences, both in Europe and in the United States, and submitted for publication in international journals with open access policy.
• Identifying efferocytosis as a trigger for controlled cytokine secretion mechanism.
• Identifying efferocytosis-stimulated cytokine secretion as a key mechanism for the homeostasis of protective cardiac resident macrophage populations.
• Identifying efferocytosis-stimulated cytokine secretion as a key mechanism to maintain cardiac homeostasis at steady state and myocardial remodelling after infarction.
• Identifying that insulin resistance, the pathophysiological mechanism leading to T2D impairs efferocytosis-stimulated cytokine secretion and leads to adverse remodelling of the infarcted myocardium.
A better understanding of the molecular mechanisms underlying macrophages’ immunomodulatory role will foster novel and efficient therapeutic strategies to restore this functionality in macrophages from diabetic patients. By restoring control over inflammation, such therapies would tremendously improve incidence of cardiovascular events and survival in patients suffering from T2D by improving post-MI remodelling.
This work will be presented to national and international conferences, both in Europe and in the United States, and submitted for publication in international journals with open access policy.
Multiple cardiac macrophage populations have recently been identified and play a major role in cardiac remodelling. However, how these cardiac resident macrophages tightly modulate inflammation and orchestrate cardiac remodelling remains elusive. The achievements of the REMAKIN project provide the first mechanistic understanding on how macrophages tightly modulate inflammation and orchestrate myocardial remodelling. Consequently, the project provides novel targets with potential therapeutic value for T2D or other chronic inflammatory diseases.