Neutrophil serine proteases: specific regulators of inflammation

Pham, Christine

doi:10.1038/nri1841

Cited by 840 publications

(753 citation statements)

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“…Although the exact mechanisms are still debatable, growing evidence has suggested that the large quantities of oxidants and proteases released by leukocytes that are recruited to sites of inflammation can overwhelm and inactivate protease inhibitors. Furthermore, a large proportion of the serine proteases that have been released from cells can bind to plasma membranes and/or ECM with their catalytic activity preserved, which makes them inaccessible, and therefore resistant, to circulating high‐molecular‐weight endogenous inhibitors 41. Therefore, NE present within atherosclerotic plaques in a compartmentalizing manner with a higher local concentration may contribute to the process of matrix degradation and the weakening of the vessel wall, which, in turn, is responsible for the atherosclerotic lesion formation.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Wen

Chen

et al. 2018

JAHA

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BackgroundTo investigate whether neutrophil elastase (NE) plays a causal role in atherosclerosis, and the molecular mechanisms involved.Methods and Results NE genetic–deficient mice (Apolipoprotein E−/−/NE −/− mice), bone marrow transplantation, and a specific NE inhibitor (GW311616A) were employed in this study to establish the causal role of NE in atherosclerosis. Aortic expression of NE mRNA and plasma NE activity was significantly increased in high‐fat diet (HFD)–fed wild‐type (WT) (Apolipoprotein E−/−) mice but, as expected, not in NE‐deficient mice. Selective NE knockout markedly reduced HFD‐induced atherosclerosis and significantly increased indicators of atherosclerotic plaque stability. While plasma lipid profiles were not affected by NE deficiency, decreased levels of circulating proinflammatory cytokines and inflammatory monocytes (Ly6Chi/CD11b+) were observed in NE‐deficient mice fed with an HFD for 12 weeks as compared with WT. Bone marrow reconstitution of WT mice with NE −/− bone marrow cells significantly reduced HFD‐induced atherosclerosis, while bone marrow reconstitution of NE −/− mice with WT bone marrow cells restored the pathological features of atherosclerotic plaques induced by HFD in NE‐deficient mice. In line with these findings, pharmacological inhibition of NE in WT mice through oral administration of NE inhibitor GW311616A also significantly reduced atherosclerosis. Mechanistically, we demonstrated that NE promotes foam cell formation by increasing ATP‐binding cassette transporter ABCA1 protein degradation and inhibiting macrophage cholesterol efflux.ConclusionsWe outlined a pathogenic role for NE in foam cell formation and atherosclerosis development. Consequently, inhibition of NE may represent a potential therapeutic approach to treating cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Wen

Chen

et al. 2018

JAHA

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“…Similarly, neutrophil-derived Cathepsin G may increase the chemotactic activity of CXCL8, CXCL5 and CCL15 through Nterminal truncation [218]. Ly6G + neutrophils are the dominant source of CXCR2 in the blood, and CXCR2 deficiency attenuates neutrophil recruitment to the tumor bed [219].…”

Section: Neutrophil Recruitment To the Tumor Microenvironmentmentioning

confidence: 99%

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

Sionov

Fridlender

Granot

2014

Cancer Microenvironment

324

261

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Neutrophils are myeloid cells that constitute 50-70 % of all white blood cells in the human circulation. Traditionally, neutrophils are viewed as the first line of defense against infections and as a major component of the inflammatory process. In addition, accumulating evidence suggest that neutrophils may also play a key role in multiple aspects of cancer biology. The possible involvement of neutrophils in cancer prevention and promotion was already suggested more than half a century ago, however, despite being the major component of the immune system, their contribution has often been overshadowed by other immune components such as lymphocytes and macrophages. Neutrophils seem to have conflicting functions in cancer and can be classified into anti-tumor (N1) and pro-tumor (N2) sub-populations. The aim of this review is to discuss the varying nature of neutrophil function in the cancer microenvironment with a specific emphasis on the mechanisms that regulate neutrophil mobilization, recruitment and activation.

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“…The mechanism(s) by which neutrophil serine proteinases participate in inflammation probably involves proteolysis of chemokines (CXCL8, CXCL2) or cytokines (pro-TNF␣, pro-interleukin-1␤ [proIL-1␤], IL-6), or modulating integrin clustering and activation of Toll-like receptor 4 and PARs (for review, see ref. 6). Such diverse biologic mechanisms further highlight the non-ECM-degrading functions of serine proteinases that have direct relevance to arthritis.…”

Section: Immune Cell-derived Serine Proteinasesmentioning

confidence: 99%

“…Some of the best-known serine proteinases have roles in the digestion of food proteins (chymotrypsin, trypsin, and elastase), blood clot formation (coagulation factors and thrombin), and fibrinolysis (plasmin). Furthermore, serine proteinases have been shown to be major players in initiating the immune responses that are thought to drive inflammation in arthritis (6,7).…”

Section: Introductionmentioning

confidence: 99%