Journal Article Ahead of print
PubMed: 41672970 DOI: 10.1038/s41419-026-08427-4
Loss of MLKL impairs abdominal aortic aneurysm development by attenuating smooth muscle cell necroptosis.
Cell Death Dis
Authors: Harshal Nemade, Dennis Mehrkens, Hannah Sophia Lottermoser, Zeynep Ece Yilmaz, Julian Mader, Patrik Schelemei, Felix Ruben Picard, Simon Geißen, Gülsah Fülgen Schwab, Friedrich Felix Hoyer, Henning Guthoff, Alexander Hof, Felix Sebastian Nettersheim, Agapios Sachinidis, Norbert Gerdes, Gerhard Sengle, Holger Winkels, Stefan Baldus, Manolis Pasparakis, Martin Mollenhauer, Matti Adam
Affiliations
- Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, Cologne, Germany.
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.
- Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, Cologne, Germany.
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.
- Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany.
- Cardiovascular Research Institute Düsseldorf (CARID), Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany.
- Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
- Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
- Cologne Center for Musculoskeletal Biomechanics (CCMB), Cologne, Germany.
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Abstract
Abdominal aortic aneurysm (AAA) is a life-threatening condition characterized by chronic vascular inflammation and progressive aortic wall deterioration. MLKL-driven necroptosis, a highly inflammatory form of cell death, has been implicated in several cardiovascular pathologies; however, its role in AAA remains incompletely understood. Using the aortic elastase-perfusion model, we investigated the impact of necroptosis deficiency on AAA progression in necroptosis-deficient transgenic mice, including RIPK1 kinase-inactive (Ripk1 D138N/D138N), MLKL knockout (Mlkl -/-), and MLKL phospho-deficient (Mlkl AA) animals. Ultrasound analysis revealed that, compared to WT animals, the necroptosis-deficient animals were protected from aneurysm formation, exhibiting preserved aortic structure, reduced immune cell infiltration, and attenuated extracellular matrix remodeling. Bulk mRNAseq revealed significant downregulation of genes associated with fibrinolysis, immune cell activation/migration, inflammation, complement and coagulation cascades in necroptosis-deficient animals. Bone marrow transplantation experiments demonstrated that MLKL deficiency in smooth muscle cells (SMCs), rather than in myeloid cells, was primarily responsible for the protective phenotype. Furthermore, consistent with previous reports, necroptosis induction in MLKL-expressing human and primary mouse SMCs led to increased secretion of proinflammatory cytokines. Live-cell imaging revealed that necroptotic SMCs promote activation and migration of HL60-differentiated polymorphonuclear neutrophils. Collectively, these findings demonstrate that necroptotic SMC death and resulting leukocyte activation play a causative role in AAA development and suggest that pharmacological inhibition of MLKL may represent a promising treatment strategy for AAA disease.
MeSH
Cells, Muscle Cells, Aortic Aneurysm, Muscles, Muscle, Smooth, Necroptosis, Aneurysm, Neutrophils, Myocytes, Smooth Muscle, Cell Death, Aortic Aneurysm, Abdominal