# Myeloid-specific knockout of Notch-1 inhibits MyD88- and TRIF-mediated TLR signaling pathways by regulating oxidative stress-SHP2 axis, thus restraining aneurysm progression

## TL;DR

Disabling Notch-1 in myeloid cells reduces aneurysm progression by lowering inflammation and oxidative stress through the SHP2 pathway.

## Contribution

This study reveals a novel mechanism by which Notch-1 regulates aneurysm progression via oxidative stress and SHP2 in myeloid cells.

## Key findings

- Myeloid-specific knockout of Notch-1 reduced aneurysm size, macrophage infiltration, and oxidative stress in mice.
- Notch-1 knockout increased SHP2 levels and decreased TLR signaling and inflammatory cytokines in aneurysm tissues.
- Macrophage phagocytic capacity was enhanced following Notch-1 knockout via the SHP2 signaling pathway.

## Abstract

Objective: Notch-1 is a signal regulatory protein with extensive effects in myeloid cells, but its role in aneurysms remains to be fully clarified. In this study, therefore, the aneurysm mouse model with myeloid-specific knockout of Notch-1 was established to observe the role of Notch-1 in aneurysm progression.

Methods and Results: The effect of Notch-1 was assessed by pathological staining and Western blotting. It was found that after myeloid-specific knockout of Notch-1 in the aneurysm mouse model, the area of aneurysms and the macrophage infiltration were significantly reduced, the damage to arterial elastic plates was significantly relieved, and the oxidative stress level significantly declined. The results of Western blotting showed that after myeloid-specific knockout of Notch-1, the levels of oxidative stress-related proteins p22 and p47 in aneurysm tissues significantly declined, accompanied by a significant increase in the protein level of Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2). In addition, the levels of phosphorylated myeloid differential protein-88 (MyD88), TIR domain-containing adaptor-inducing interferon-β (TRIF) and nuclear factor-κB (NF-κB), and inflammatory cytokines interferon-γ (IFN-γ), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) also significantly decreased after myeloid-specific knockout of Notch-1. Following myeloid-specific knockout of Notch-1, the phagocytic capacity of macrophages was enhanced by promoting the SHP2 signaling pathway.

Conclusion: Notch-1 in monocytes/macrophages can activate the Toll-like receptor (TLR)-mediated inflammatory and stress responses by activating oxidative stress and inhibiting the SHP2 protein expression, thus facilitating aneurysm progression.