α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8

Bergin, David A.; Reeves, Emer P.; Meleady, Paula; Henry, Michael; McElvaney, Oliver J; Carroll, Tomás P.; Condron, Claire; Chotirmall, Sanjay H.; Clynes, Martin; O’Neill, Shane; McElvaney, Noel G.

doi:10.1172/jci41196

Cited by 254 publications

(335 citation statements)

References 83 publications

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“…In contrast, however, LTB 4 did not bind the AAT cleavage product, C-36. Moreover, we have previously demonstrated the importance of AAT glycosylation motifs for IL-8 binding (29), but in contrast, results of the present study indicate that recombinant nonglycosylated AAT successfully binds LTB 4 . The representative UV spectra profiles in Fig.…”

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confidence: 99%

“…In light of our previous publications demonstrating the ability of AAT to inhibit IL-8-and TNF-a-induced neutrophil responses (28,29), we assessed the capacity of AAT to act as a novel LTB 4 antagonist. Initial studies examined the effect of AAT on neutrophil adhesion.…”

Section: Aat Modulates Ltb 4 -Induced Neutrophil Adhesion and Degranumentioning

confidence: 99%

“…Indeed, studies indicate that AAT can modulate activity of a number of cell types, including neutrophils (28,29), macrophages (30,31), pancreatic islet b cells (32), B cells (33) and mast cells (34). AAT deficiency (AATD) is a hereditary disorder characterized by low circulating levels of AAT and increased airway levels of LTB 4 (35).…”

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confidence: 99%

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The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

O’Dwyer

O’Brien

Wormald

et al. 2015

The Journal of Immunology

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Leukotriene B4 (LTB4) contributes to many inflammatory diseases, including genetic and nongenetic forms of chronic obstructive pulmonary disease. α-1 Antitrypsin (AAT) deficiency (AATD) is characterized by destruction of lung parenchyma and development of emphysema, caused by low AAT levels and a high neutrophil burden in the airways of affected individuals. In this study we assessed whether AATD is an LTB4-related disease and investigated the ability of serum AAT to control LTB4 signaling in neutrophils. In vitro studies demonstrate that neutrophil elastase is a key player in the LTB4 inflammatory cycle in AATD, causing increased LTB4 production, and associated BLT1 membrane receptor expression. AATD patients homozygous for the Z allele were characterized by increased neutrophil adhesion and degranulation responses to LTB4. We demonstrate that AAT can bind LTB4 and that AAT/LTB4 complex formation modulates BLT1 engagement and downstream signaling events, including 1,4,5-triphosphate production and Ca2+ flux. Additionally, treatment of ZZ-AATD individuals with AAT augmentation therapy decreased plasma LTB4 concentrations and reduced levels of membrane-bound neutrophil elastase. Collectively, these results provide a mechanism by which AAT augmentation therapy impacts on LTB4 signaling in vivo, and not only reinforces the utility of this therapy for resolving inflammation in AATD, but supports useful future clinical applications in treatment of other LTB4-related diseases.

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confidence: 99%

Section: Aat Modulates Ltb 4 -Induced Neutrophil Adhesion and Degranumentioning

confidence: 99%

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The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

O’Dwyer

O’Brien

Wormald

et al. 2015

The Journal of Immunology

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“…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: Discussionmentioning

confidence: 99%

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

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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...

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“…In the present study, we showed that AAT reduced RANKL-induced TNF-α production. One possible mechanism is that AAT inhibits ADAM17, also known as a TNF-α-converting enzyme, which cleaves and releases soluble TNF-α (39). A recent study by Bergin et al (32) showed that AAT can reduce the binding of TNF-α to its receptors (TNFR1 and TNFR2).…”

Section: Aat Inhibited Catk Activity and Rankl-induced Catk Gene Exprmentioning

confidence: 99%

α-1 Antitrypsin Inhibits RANKL-induced Osteoclast Formation and Functions

Akbar

Nardo

Chen

et al. 2017

Mol Med

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Osteoporosis is a global public health problem affecting more than 200 million people worldwide. We previously showed that treatment with α-1 antitrypsin (AAT), a multifunctional protein with antiinflammatory properties, mitigated bone loss in an ovariectomized mouse model. However, the underlying mechanisms of the protective effect of AAT on bone tissue are largely unknown. In this study, we investigated the effect of AAT on osteoclast formation and function in vitro. Our results showed that AAT dose-dependently inhibited the formation of receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclasts derived from mouse bone marrow macrophage/monocyte (BMM) lineage cells and the RAW 264.7 murine macrophage cell line. To elucidate the possible mechanisms underlying this inhibition, we tested the effect of AAT on the gene expression of cell surface molecules, transcription factors and cytokines associated with osteoclast formation. We showed that AAT inhibited macrophage colony-stimulating factor (M-CSF)-induced cell surface RANK expression in osteoclast precursor cells. In addition, AAT inhibited RANKL-induced TNF-α production, cell surface CD9 expression and dendritic cell-specific transmembrane protein (DC-STAMP) gene expression. Importantly, AAT treatment significantly inhibited osteoclast-associated mineral resorption. Together, these results uncover new mechanisms for the protective effects of AAT and strongly support the notion that AAT has therapeutic potential for the treatment of osteoporosis.

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α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8

Cited by 254 publications

References 83 publications

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

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

α-1 Antitrypsin Inhibits RANKL-induced Osteoclast Formation and Functions

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