Periodic Reporting for period 3 - ImAgine (Exploring the link between innate Immunity and cellular Aging)
Reporting period: 2022-01-01 to 2023-06-30
What is the problem/issue being addressed?
The ability to fight infection through the orchestrated action of our innate immune system is essential for survival. However, as brutally demonstrated by the fatality of COVID-19, if the innate immune response becomes out of balance, it can in itself severely aggravate and accelerate diseases processes – with ultimately detrimental outcome. Aberrant inflammation can affect all organs of the body and, as a secondary component of many diseases it often requires medical intervention to restrict or end inflammation-triggered damage. Ageing and age-related diseases share some basic pathomechanisms that largely converge on inflammation. During ageing, chronic, sterile, low-grade inflammation develops, which contributes to the pathogenesis of age-related diseases. The number of people suffering from age-related inflammatory diseases such as cardiovascular diseases, neurodegeneration, respiratory diseases, autoimmune diseases, and cancers has increased dramatically over the last decades. In fact, chronic inflammatory diseases have been recognized as the most significant cause of death in the world today, with more than 50% of all deaths being attributable to inflammation-related diseases 1. Together, these aspects underscore the urgency to achieve a better understanding of the fundamental immunological processes that underpin inflammatory processes and the importance to identify and characterize key (protein) targets for the development of new and more efficient anti-inflammatory medicines.
Why is it important for society?
Inflammatory diseases adversely affect patients in terms of physical suffering and pain and have a huge impact on the quality of life. In addition to the impact on each individual and the immediate social network, inflammatory diseases also have a huge burden on society owing to high direct and indirect healthcare costs, respectively. Research and development of new medicines for the treatment of inflammatory disorders, can therefore have a revolutionary and long-lasting impact on society. This project has the potential to lay the foundation for a new opportunity in drug discovery towards better treatments for inflammatory diseases with unmet medical need.
What are the overall objectives?
From a molecular perspective, inflammation is triggered by activation of diverse innate immune signaling pathways. Research over the past decade has found that the cGAS-STING pathway, which responds to DNA, is a key player driving sterile inflammation in the context of many common age-associated inflammatory conditions. This project seeks to provide new insight into the links between mechanisms of aging and chronic inflammation. A particular focus is on the role of the cGAS-STING pathway in driving age-related phenotypes and the underlying molecular mechanisms. Beyond offering new knowledge about basic immunological principals that are playing a role in the ageing process, this project has the potential to uncover new drug targets for a more efficient treatment of chronic inflammatory conditions.
The ability to fight infection through the orchestrated action of our innate immune system is essential for survival. However, as brutally demonstrated by the fatality of COVID-19, if the innate immune response becomes out of balance, it can in itself severely aggravate and accelerate diseases processes – with ultimately detrimental outcome. Aberrant inflammation can affect all organs of the body and, as a secondary component of many diseases it often requires medical intervention to restrict or end inflammation-triggered damage. Ageing and age-related diseases share some basic pathomechanisms that largely converge on inflammation. During ageing, chronic, sterile, low-grade inflammation develops, which contributes to the pathogenesis of age-related diseases. The number of people suffering from age-related inflammatory diseases such as cardiovascular diseases, neurodegeneration, respiratory diseases, autoimmune diseases, and cancers has increased dramatically over the last decades. In fact, chronic inflammatory diseases have been recognized as the most significant cause of death in the world today, with more than 50% of all deaths being attributable to inflammation-related diseases 1. Together, these aspects underscore the urgency to achieve a better understanding of the fundamental immunological processes that underpin inflammatory processes and the importance to identify and characterize key (protein) targets for the development of new and more efficient anti-inflammatory medicines.
Why is it important for society?
Inflammatory diseases adversely affect patients in terms of physical suffering and pain and have a huge impact on the quality of life. In addition to the impact on each individual and the immediate social network, inflammatory diseases also have a huge burden on society owing to high direct and indirect healthcare costs, respectively. Research and development of new medicines for the treatment of inflammatory disorders, can therefore have a revolutionary and long-lasting impact on society. This project has the potential to lay the foundation for a new opportunity in drug discovery towards better treatments for inflammatory diseases with unmet medical need.
What are the overall objectives?
From a molecular perspective, inflammation is triggered by activation of diverse innate immune signaling pathways. Research over the past decade has found that the cGAS-STING pathway, which responds to DNA, is a key player driving sterile inflammation in the context of many common age-associated inflammatory conditions. This project seeks to provide new insight into the links between mechanisms of aging and chronic inflammation. A particular focus is on the role of the cGAS-STING pathway in driving age-related phenotypes and the underlying molecular mechanisms. Beyond offering new knowledge about basic immunological principals that are playing a role in the ageing process, this project has the potential to uncover new drug targets for a more efficient treatment of chronic inflammatory conditions.
To function properly innate immune signaling pathways necessitate tight regulation. Malfunctioning of regulatory mechanisms of innate immune signaling is associated with uncontrolled inflammatory responses, which are hallmarks of ageing-related diseases. Accordingly, a key research priority is to define the molecular mechanisms by which cells achieve control over cellular signaling pathways to regulate and terminate innate immune responses. Within this project we have pioneered understanding of the cross-talk between innate DNA immunity and its regulation on genomic self-DNA. As such, we have worked out cellular safeguard mechanisms that function to restrict cGAS from sensing a cell`s own DNA and, thus, prevent autoreactivity. More specifically, we have defined that both chromatin architectural proteins, exemplified by BAF, as well as the nucleosome - the basic unit of chromatin found inside the nucleus - exert potent inhibitory effects over the innate DNA sensing protein cGAS. Together, these studies explained most fundamental mechanisms that safeguard cells from mounting abnormal inflammatory responses and they inspire the development of new ways to manipulate cGAS-STING signaling in a desired fashion. Ongoing work based on these discoveries now aims to better understand how the here uncovered mechanisms related to chronic inflammatory phenotypes observed during ageing.
Despite considerable progress into the molecular complexity of innate immune signaling, it remains incompletely understood how cells are able to control and regulate immune response to DNA – a ubiquitous molecule. Our project has elucidated fundamental principles of the regulation of cGAS-dependent innate immunity. Given that the cGAS-STING pathway emerges as a central driver of common inflammatory conditions associated with ageing understanding the mechanistic basis of its regulation is highly valuable. Not only will it create new opportunities to understand the basis for aberrant ageing phenotypes, but it will also help to design new interventions into more effective treatments of ageing-associated inflammation.