Neuraminidase 1 Exacerbating Aortic Dissection by Governing a Pro-Inflammatory Program in Macrophages

Abstract

Inflammation plays an important role in aortic dissection (AD). Macrophages are critically involved in the inflammation after aortic injury. Neuraminidases (NEUs) are a family of enzymes that catalyze the cleavage of terminal sialic acids from glycoproteins or glycolipids, which is emerging as a regulator of macrophage-associated immune responses. However, the role of neuraminidase 1 (NEU1) in pathological vascular remodeling of AD remains largely unknown. This study sought to characterize the role and identify the potential mechanism of NEU1 in pathological aortic degeneration. After β-aminopropionitrile monofumarate (BAPN) administration, NEU1 elevated significantly in the lesion zone of the aorta. Global or macrophage-specific NEU1 knockout (NEU1 CKO) mice had no baseline aortic defects but manifested improved aorta function, and decreased mortality due to aortic rupture. Improved outcomes in NEU1 CKO mice subjected to BAPN treatment were associated with the ameliorated vascular inflammation, lowered apoptosis, decreased reactive oxygen species production, mitigated extracellular matrix degradation, and improved M2 macrophage polarization. Furthermore, macrophages sorted from the aorta of NEU1 CKO mice displayed a significant increase of M2 macrophage markers and a marked decrease of M1 macrophage markers compared with the controls. To summarize, the present study demonstrated that macrophage-derived NEU1 is critical for vascular homeostasis. NEU1 exacerbates BAPN-induced pathological vascular remodeling. NEU1 may therefore represent a potential therapeutic target for the treatment of AD.

Non-steroidal anti-inflammatory drug target gene associations with major depressive disorders: a Mendelian randomisation study integrating GWAS, eQTL and mQTL Data

“…Recently, it was shown that NEU1 regulated toll-like receptor (TLR) activation on macrophages; specifically, ligand binding to TLRs induced NEU1 activity and led to receptor activation, nitric oxide and proinflammatory cytokine production [47]. Importantly, these NEU1 roles in macrophages are confirmed by several in vitro studies [47][48][49][50][51].…”

Lipoprotein sialylation in atherosclerosis: Lessons from mice

“…These opposing functions of protein sialylation depend upon the target substrate molecules and the locations where the modification is regulated. Recent studies in mice using BM transplantation or monocyte-specific Cre-LoxP system have uncovered the key function of neuraminidases and sialyltransferases in monocytes and macrophages ( 80 , 90 , 94 , 120 , 123 ). More studies are needed to address the importance of protein sialylation using mice with additional tissue- and cell-type-specific targeting of the machinery, including endothelial cells and vascular smooth muscle cells.…”

Neuraminidases—Key Players in the Inflammatory Response after Pathophysiological Cardiac Stress and Potential New Therapeutic Targets in Cardiac Disease

“…A reduction of cell surface sialylation to a normal level via exogenous NEU1 restored phagocytosis. NEU1 desialylates cell surface receptors such as Fc receptors for immunoglobulin G, and thus activates phagocytosis in macrophages and dendritic cells [ 73 , 74 ].…”

“…Since monocytes/macrophages feature the wound healing process as well as inflammatory processes, a balance between both is essential [ 105 , 106 , 107 , 108 ]. As described above, NEU1 promotes the pro-inflammatory phenotype of monocytes/macrophages [ 32 , 74 ] ( Figure 2 ), thereby affecting immune reactions and myocardial damage following an ischemic insult. It was recently shown that NEU1, upregulated early in the ischemic [ 27 ] and infarcted [ 109 ] area, significantly contributes to the development of heart failure following ischemia/reperfusion (I/R) injury in mice with a cardiomyocyte-specific overexpression of NEU1.…”