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Necroptosis in aortic aneurysm disease - significance of inflammation in MLKL dependent cell death

Abdominal aortic aneurysm (AAA) disease is common and associated with high lethality if complications, like aortic rupture, occur. The development of therapeutic options to inhibit the development or progression of AAA is, therefore, of high clinical importance. Loss of smooth muscle cells (SMC) in the tunica media of the aortic wall represents a central event in the development of AAA. Recently, apoptotic cell death has been suggested to be a critical mechanism of SMC degradation in this disease. Apoptosis is a well-characterized form of regulated cell death, which is orchestrated by a family of cysteine proteases known as caspases. Apoptosis was considered, for many years, to be the only type of regulated cell death, with necrosis being described as ‘accidental’ cell death. However, recent research has identified new pathways for molecularly regulated necrotic cell death, known as necroptosis. Necroptosis is a type of regulated necrotic cell death that is induced by receptor-interacting kinases 1 and - 3 (RIPK1/3) and the substrate of RIPK3, mixed lineage kinase-like (MLKL). In contrast to apoptosis, necroptosis serves as a potent inducer of inflammation and has been linked to inflammatory diseases of the skin and the gut, as well as chronic liver inflammation and the development of liver carcinoma.
The formation of AAA is also a highly inflammatory process. Progressive dilation of the aorta is associated with the recruitment and activation of leukocytes (e.g. polymorphonuclear neutrophils (PMN)). One of the major neutrophil effector proteins, the heme-enzyme myeloperoxidase (MPO), uses H2O2 as a co-substrate, is capable of oxidizing halides (in particular chloride, thereby generating the potent oxidant HOCl), and shows high avidity to the vessel wall. Furthermore, MPO has evolved as a critical regulator of local and vascular inflammation, activates extracellular matrix (ECM) remodeling proteases like matrix-metalloprotease 2, 7, and 9, and promotes apoptosis via p38 MAP-kinase dependent pathways. Aneurysm formation is furthermore nurtured by other leukocyte-derived enzyme systems, which account for the release of cytokines, matrix remodeling proteases, and generation of reactive oxygen species (ROS). Whereas leukocytes are an established contributor to AAA progression, the role of necroptosis in this disease remains unclear. Whether necroptotic stimuli in the early phase of AAA formation activate leukocytes, or whether the recruitment of leukocytes critically drives the extent of aneurysm formation by induction of additional necroptosis, remains to be elucidated. This could imply a vicious circle of inflammation and necroptosis, potentially resulting in AAA formation.

We hypothesize that innate immune cells, namely PMN, induce aortic SMC necroptosis, which in turn enhances vascular inflammation in a “vicious circle”. Thus, necroptosis might strongly contribute to the development of AAA.

In Aim 1, we will focus on the role of necroptotic cell death pathways on vascular phenotypic changes in AAA formation. We will analyze aneurysm progression in mice lacking the specific necroptosis executing protein MLKL (Mlkl-/-) in vivo. Aim 2 will clarify how necroptosis drives the innate immune response in AAA and will determine the underlying mechanisms and extent of neutrophil recruitment and activation, since necroptosis not only enhances but is also induced by inflammation. Aim 3 will assess whether and how neutrophil-derived oxidants induce necroptosis in AAA.
In summary, this project will elucidate the role of necroptosis, the effect of necroptosis on recruitment and activation of leukocytes, and the role of vascular inflammatory mediators on necroptosis as critical drivers of AAA formation. This may ultimately help to identify necroptosis and its mediator MLKL as a potential pharmacologic target for this disease.



B05 Hypothesis: Leukocyte activation during AAA formation induces SMC necroptosis thereby further driving inflammation and subsequent necroptosis in a “vicious circle”.

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