Opening the flood-gates: how neutrophil-endothelial interactions regulate permeability

Distasi, Matthew R.; Ley, Klaus

doi:10.1016/j.it.2009.07.012

Cited by 195 publications

(172 citation statements)

References 120 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…It is known that AAT suppresses neutrophil function, including IL-8 release and adherence to endothelial cells (24,25). Indeed, the absence of elastase had no effect on neutrophil recruitment (26), which supports our findings. Circulating AAT enters cells (27) and can act as an inhibitor for matriptase (28), caspases-1 and -3 (29,30), TNF-α-converting enzyme (31), and intracellular calpain I (32).…”

Section: Discussionsupporting

confidence: 91%

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Jonigk

Al-Omari²,

Maegel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

227

148

View full text Add to dashboard Cite

The rationale of α1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastasedeficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF-α (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-α, DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1β gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastasedeficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40-to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.is the prototypic member of the serpin superfamily and one of the most abundant serine protease inhibitors in the circulation (1). As an acute-phase protein, AAT is thought to play an important role in limiting host-tissue injury triggered by proteases, particularly neutrophil elastase (NE). The clinical relevance of AAT is highlighted in individuals with inherited deficiency in circulating AAT, who have increased susceptibility to early-onset pulmonary emphysema, liver and pancreatic diseases, and in rare cases to panniculitis and vasculitis (2). It has been assumed that in AAT-deficiency the protease/antiprotease balance is shifted toward NE, which leads to extensive tissue damage, particularly in causing emphysema. Therefore, augmentation of circulating AAT was introduced 25 y ago to treat emphysema patients with severe PiZZ (Glu342Lys) AAT deficiency (3). Because clinical trials of AAT augmentation therapy use historical data as controls, the benefit of AAT therapy for PiZZ patients remains under debate (4-6), although in most cases therapy offers disease stabilization. The uncertainty surrounding the efficacy of augmentation therapy also reflects the incomplete understanding of the properties of the AAT protein, which can be affected by the isolation methods from plasma.Although the a...

show abstract

Section: Discussionsupporting

confidence: 91%

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Jonigk

Al-Omari²,

Maegel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

227

148

View full text Add to dashboard Cite

show abstract

“…Interestingly, neutrophils release CCL20 under inflammatory conditions, and this chemokine is implicated in a reciprocal activation and recruitment pattern between human neutrophils and Th17 cells (30,84). Because of their capacity to produce and secrete a broad array of molecules and given their rapid deployment to sites of inflammation, neutrophils have emerged as likely contributors to the disruption of blood-CNS barriers induced in EAE (28,63,(85)(86)(87)(88).…”

Section: Discussionmentioning

confidence: 99%

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Aubé

Lévesque

Paré

et al. 2014

The Journal of Immunology

186

159

View full text Add to dashboard Cite

Disruption of the blood–brain and blood–spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP+ myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP+ cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.

show abstract

“…This possibility is supported by reports describing diminished endothelial barrier function, resulting from junctional disassembly and cytoskeletal reorganization, following the ligation of neutrophil adhesion molecules with their counterreceptors on endothelial cells, such as the binding of b-2 integrins with either ICAM-1 or VCAM-1. 83,90,91 It has also been proposed that neutrophils can diminish barrier function due to physical disruption of the paracellular pathway caused by the passage of these cells through the junctions. 92,93 This appears to occur despite the fact that endothelial cells can extend projections to envelop the migrating neutrophils, forming endothelial domes, with the leakage response resulting from the transfer of entrapped plasma proteins within the "dome."…”

Section: Leukocytes and Endothelial Barrier Functionmentioning

confidence: 99%

Blood cells and endothelial barrier function

2015

View full text Add to dashboard Cite

Opening the flood-gates: how neutrophil-endothelial interactions regulate permeability

Cited by 195 publications

References 120 publications

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Blood cells and endothelial barrier function

Contact Info

Product

Resources

About