Effect of soluble cleavage products of important receptors/ligands on efferocytosis: Their role in inflammatory, autoimmune and cardiovascular disease.
1区 · 医学
作者: Amir Tajbakhsh ; Seyed Mohammad Gheibi Hayat ; Alexandra E Butler ; Amirhossein Sahebkar
Efferocytosis, the clearance of apoptotic cells (ACs), is a physiologic, multifaceted and dynamic process and a fundamental mechanism for the preservation of tissue homeostasis by avoiding unwanted inﬂammation and autoimmune responses through special phagocytic receptors. Defective efferocytosis is associated with several disease states, including cardiovascular disease and impaired immune surveillance, as occurs in cancer and autoimmune disease. A major cause of defective efferocytosis is non-functionality of surface receptors on either the phagocytic cells or the ACs, such as TAM family tyrosine kinase, which turns to a soluble form by cleavage/shedding or alternative splicing. Recently, soluble forms have featured prominently as potential biomarkers, indicative of prognosis and enabling targeted therapy using several commonly employed drugs and inhibitors, such as bleomycin, dexamethasone, statins and some matrix metalloproteinase inhibitors such as TAPI-1 and BB3103. Importantly, to design drug carriers with enhanced circulatory durability, the adaptation of soluble forms of physiological receptors/ligands has been purported. Research has shown that soluble forms are more effective than antibody forms in enabling targeted treatment of certain conditions, such as autoimmune diseases. In this review, we sought to summarize the current knowledge of these soluble products, how they are generated, their interactions, roles, and their potential use as biomarkers in prognosis and treatment related to inflammatory, cardiovascular, and autoimmune diseases.
2009-05-01·Clinical and Experimental Immunology3区 · 医学
Tumour necrosis factor-α processing in interstitial lung disease: a potential role for exogenous proteinase-3
3区 · 医学
作者: Armstrong, L. ; Godinho, S. I. H. ; Uppington, K. M. ; Whittington, H. A. ; Millar, A. B.
Tumour necrosis factor (TNF) blockade has become an important immunomodulatory therapy, particularly in patients refractory to conventional immunosuppression, but responses can be unpredictable. Understanding the complex biology of TNF processing may be key to predicting such responses and reduce unwanted side effects. TNF bioavailability is regulated partly by TNF-alpha converting enzyme (TACE) cleavage; however, it can also be cleaved by proteinase-3 (PR-3). We have demonstrated this mechanism previously in healthy human alveolar macrophages (AM), leading us to hypothesize that PR-3-mediated TNF processing may be an important mechanism in inflammatory lung disease. Furthermore, this may be more apparent in diseases with a neutrophil component typical of usual interstitial pneumonia (UIP), compared with sarcoidosis, where lymphocytes predominate. We isolated AM from patients with UIP and sarcoidosis and healthy subjects. We found increased TACE expression on AM in sarcoidosis. In contrast, TACE was not increased in UIP; we found increased cleavage of glutathione S-transferase-proTNF) substrate, relative to both sarcoidosis and healthy controls. Furthermore, cleavage was subject to inhibition by serine protease inhibitor, rather than a TACE inhibitor BB-3103. Cleavage was proportional to the number of neutrophils isolated from bronchoalveolar lavage, whereas there was an inverse relationship between neutrophils and BB-3103 inhibition. There was also increased PR-3 on the AM surface in UIP relative to healthy controls. These data provide evidence for PR-3-mediated cleavage in UIP, which may have implications for future therapeutic targeting of TACE.
2006-12-01·FASEB Journal2区 · 生物学
Diapedesis of monocytes is associated with MMP-mediated occludin disappearance in brain endothelial cells
2区 · 生物学
作者: Reijerkerk, Arie ; Kooij, Gijs ; van der Pol, Susanne M. A. ; Khazen, Shadi ; Dijkstra, Christine D. ; de Vries, Helga E.
The blood-brain barrier (BBB), a selective barrier formed by endothelial cells and dependent on the presence of tight junctions, is compromised during neuroinflammation. A detailed study of tight junction dynamics during transendothelial migration of leukocytes has been lacking. Therefore, we retrovirally expressed green fluorescent protein (GFP) fused to the N-terminus of the tight junction protein occludin in the rat brain endothelial cell line GP8/3.9. Confocal microscopy analyses revealed that GFP-occludin colocalized with the intracellular tight junction protein, ZO-1, localized at intercellular connections, and was absent at cell borders lacking apposing cells. Using live cell imaging we found that monocytes scroll over the brain endothelial cell surface toward cell-cell contacts, induce gap formation, which is associated with local disappearance of GFP-occludin, and subsequently traverse the endothelium paracellularly. Immunoblot analyses indicated that loss of occludin was due to protein degradation. The broad spectrum matrix metalloproteinase (MMP) inhibitor BB-3103 significantly inhibited endothelial gap formation, occludin loss, and the ability of monocytes to pass the endothelium. Our results provide a novel insight into the mechanism by which leukocytes traverse the BBB and illustrate that therapeutics aimed at the stabilization of the tight junction may be beneficial to resist a neuroinflammatory attack.