Journal Article

NINJ1 Facilitates Abdominal Aortic Aneurysm Formation via Blocking TLR4‐ANXA2 Interaction and Enhancing Macrophage Infiltration

Qiu, Peng, Wang, Xin, Qin, Jinbao, Xu, Zhijue, Lu, Xinwu, Li, Bo, Ding, Ang'ang, Zeng, Chenlin, Wu, Zhaoyu, Pu, Hongji, Hu, Jiateng, Wu, Xiaoyu, Lei, Jiahao

2024

Overview

Abdominal aortic aneurysm (AAA) is a common and potentially life‐threatening condition. Chronic aortic inflammation is closely associated with the pathogenesis of AAA. Nerve injury‐induced protein 1 (NINJ1) is increasingly acknowledged as a significant regulator of the inflammatory process. However, the precise involvement of NINJ1 in AAA formation remains largely unexplored. The present study finds that the expression level of NINJ1 is elevated, along with the specific expression level in macrophages within human and angiotensin II (Ang II)‐induced murine AAA lesions. Furthermore, Ninj1flox/flox and Ninj1flox/floxLyz2‐Cre mice on an ApoE−/− background are generated, and macrophage NINJ1 deficiency inhibits AAA formation and reduces macrophage infiltration in mice infused with Ang II. Consistently, in vitro suppressing the expression level of NINJ1 in macrophages significantly restricts macrophage adhesion and migration, while attenuating macrophage pro‐inflammatory responses. Bulk RNA‐sequencing and pathway analysis uncover that NINJ1 can modulate macrophage infiltration through the TLR4/NF‐κB/CCR2 signaling pathway. Protein‐protein interaction analysis indicates that NINJ1 can activate TLR4 by competitively binding with ANXA2, an inhibitory interacting protein of TLR4. These findings reveal that NINJ1 can modulate AAA formation by promoting macrophage infiltration and pro‐inflammatory responses, highlighting the potential of NINJ1 as a therapeutic target for AAA. NINJ1 is highly expressed in macrophages within human and murine abdominal aortic aneurysm (AAA) lesions, which enhances macrophage infiltration through the TLR4/NF‐κB/CCR2 signaling pathway, thus facilitating AAA formation. NINJ1 activates TLR4 by competitively binding with ANXA2, an inhibitory interacting protein of TLR4. This study highlights the potential of NINJ1 as a therapeutic target for AAA.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Abdomen / abdominal aortic aneurysm / Angiotensin II - metabolism / Animals / Annexin A2 - genetics / Annexin A2 - metabolism / Aortic Aneurysm, Abdominal - genetics / Aortic Aneurysm, Abdominal - metabolism / Aortic Aneurysm, Abdominal - pathology / Aortic aneurysms / Apoptosis / Cell Adhesion Molecules, Neuronal - genetics / Cell Adhesion Molecules, Neuronal - metabolism / Coronary vessels / Cytokines / Disease Models, Animal / Genes / Humans / infiltration / Inflammation / macrophage / Macrophages - metabolism / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Nerve Growth Factors / NINJ1 / Pathogenesis / Signal Transduction - genetics / Spleen / Toll-Like Receptor 4 - genetics / Toll-Like Receptor 4 - metabolism