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Anti-Inflammatory Actions of Soluble Ninjurin-1 Ameliorate Atherosclerosis

 Sejin Jeon  ;  Tae Kyeong Kim  ;  Se-Jin Jeong  ;  In-Hyuk Jung  ;  Nayoung Kim  ;  Mi-Ni Lee  ;  Seong-Keun Sonn  ;  Seungwoon Seo  ;  Jing Jin  ;  Hyae Yon Kweon  ;  Sinai Kim  ;  Dahee Shim  ;  Young Mi Park  ;  Sang-Hak Lee  ;  Kyu-Won Kim  ;  Myron I Cybulsky  ;  Hyunbo Shim  ;  Tae-Young Roh  ;  Woong-Yang Park  ;  Hae-Ock Lee  ;  Jae-Hoon Choi  ;  Sung Ho Park  ;  Goo Taeg Oh 
 CIRCULATION, Vol.142(18) : 1736-1751, 2020-11 
Journal Title
Issue Date
Ninj1 protein, mouse ; atherosclerosis ; coronary artery disease ; inflammation ; macrophages ; matrix metalloproteinase 9
Background: Macrophages produce many inflammation-associated molecules, released by matrix metalloproteinases, such as adhesion molecules, and cytokines, as well, which play a crucial role in atherosclerosis. In this context, we investigated the relationship between Ninjurin-1 (Ninj1 [nerve injury-induced protein]), a novel matrix metalloproteinase 9 substrate, expression, and atherosclerosis progression.

Methods: Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from patients with coronary artery disease and healthy controls, and atheroprone apolipoprotein e-deficient (Apoe-/-) and wild-type mice, as well. Apoe-/- mice lacking systemic Ninj1 expression (Ninj1-/-Apoe-/-) were generated to assess the functional effects of Ninj1. Bone marrow transplantation was also used to generate low-density lipoprotein receptor-deficient (Ldlr-/-) mice that lack Ninj1 specifically in bone marrow-derived cells. Mice were fed a Western diet for 5 to 23 weeks, and atherosclerotic lesions were investigated. The anti-inflammatory role of Ninj1 was verified by treating macrophages and mice with the peptides Ninj11-56 (ML56) and Ninj126-37 (PN12), which mimic the soluble form of Ninj1 (sNinj1).

Results: Our in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1-deficient macrophages promoted proinflammatory gene expression by activating mitogen-activated protein kinase and inhibiting the phosphoinositide 3-kinase/Akt signaling pathway. Whole-body and bone marrow-specific Ninj1 deficiencies significantly increased monocyte recruitment and macrophage accumulation in atherosclerotic lesions through elevated macrophage-mediated inflammation. Macrophage Ninj1 was directly cleaved by matrix metalloproteinase 9 to generate a soluble form that exhibited antiatherosclerotic effects, as assessed in vitro and in vivo. Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages, thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of this disorder in mice, regardless of the presence of Ninj1.

Conclusions: Ninj1 is a novel matrix metalloproteinase 9 substrate in macrophages, and sNinj1 is a secreted atheroprotective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis. Moreover, sNinj1-mediated anti-inflammatory effects are conserved in human macrophages and likely contribute to human atherosclerosis.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Sang Hak(이상학) ORCID logo https://orcid.org/0000-0002-4535-3745
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