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, Anti-Inflammatory Actions of Soluble Ninjurin-1 Ameliorate Atherosclerosis, Circulation. 2020;142:1736–1751.

https://doi.org/10.1161/CIRCULATIONAHA.120.046907

*Online news introducing the article (Korean)

https://www.mk.co.kr/news/it/view/2020/11/1181692/

http://www.dhnews.co.kr/news/articleView.html?idxno=131729

https://www.fnnews.com/news/202011171436277727

http://www.veritas-a.com/news/articleView.html?idxno=345817

An anti-inflammatory effect of soluble Ninjurin-1 ameliorates atherosclerosis

Macrophages play central roles in all stages of atherosclerosis, which is a chronic inflammatory disease associated with significant morbidity and mortality. Activated macrophage producing cytokines and chemokines are substrates that can be proteolytically cleaved by matrix metalloproteinase 9 (MMP9), and these molecules affect the development of cardiovascular disease. In this regard, there is a paucity of knowledge regarding macrophage-derived anti-inflammatory molecules, their mechanism of action and potential as therapeutics. Ninjurin-1 (nerve injury-induced protein 1, Ninj1), which was originally identified as a small adhesion molecule, is up-regulated in many inflammatory diseases and predicted in vitro to undergo proteolytic cleavage by MMP9 to yield a soluble form (sNinj1).
In this study, we conclusively showed that there is a correlation between Ninj1 expression from aortic macrophages and the extent of human and mouse atherosclerotic lesions. Single cell RNA sequencing (scRNA-seq) data showed great abundance of Ninj1-expressing cells in monocytes and anti-inflammatory macrophages among alternatively activated macrophages (AAMs).
Remarkably, Ninj1 deficient macrophages promoted pro-inflammatory gene expression by activating mitogen-activated protein kinase (MAPK) and inhibiting phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. This was in line with increased monocyte recruitment and the macrophage accumulation in atherosclerotic lesions. Macrophage Ninj1 was directly cleaved by MMP9 to generate a soluble form (sNinj1) that exhibited anti-atherosclerotic effects, as assessed in vitro and in vivo. Treatment with the peptides, ML56 and PN12, as sNinj1 mimics reduced pro-inflammatory gene expression in human and mouse classically activated macrophages (CAMs), attenuating monocyte transendothelial migration. Moreover, the continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammatory characteristics of this disorder in mice, regardless of the presence of Ninj1.
In summary, Ninj1 is a novel MMP9 substrate of plaque macrophages and sNinj1 is a secreted atheroprotective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis. Because soluble Ninj1-mediated anti-inflammatory effects are conserved in humans, soluble Ninj1 mimetics could be useful therapies for coronary artery disease.