# Loss of MLKL impairs abdominal aortic aneurysm development by attenuating smooth muscle cell necroptosis

## TL;DR

This study shows that MLKL-driven necroptosis in smooth muscle cells contributes to abdominal aortic aneurysm development, suggesting that inhibiting MLKL could be a potential treatment.

## Contribution

The study identifies smooth muscle cell necroptosis, specifically via MLKL, as a key driver of abdominal aortic aneurysm progression.

## Key findings

- Necroptosis-deficient mice showed reduced aneurysm formation and preserved aortic structure.
- MLKL deficiency in smooth muscle cells, not myeloid cells, was responsible for protection against AAA.
- Necroptotic smooth muscle cells promote immune cell activation and migration, contributing to AAA.

## 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 (Ripk1D138N/D138N), MLKL knockout (Mlkl−/−), and MLKL phospho-deficient (MlklAA) 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.