Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia–reperfusion injury

Toldo, Stefano; Seropián, Ignacio M.; Mezzaroma, Eleonora; Tassell, Benjamín W. Van; Salloum, Fadi N.; Lewis, Eli C.; Voelkel, Norbert F.; Dinarello, Charles A.; Abbate, Antonio

doi:10.1016/j.yjmcc.2011.05.003

Cited by 130 publications

(143 citation statements)

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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.

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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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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.

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227

148

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“…In animal models of myocardial ischemia/reperfusion and infarction, administration of AAT reduced infarction area, improved left ventricular function, and reduced cellular apoptosis, caspase activation, and leukocyte infiltration 16. Analogous beneficial effects have been described in a growing number of other models of IRI in situ and in additional transplant models.…”

Section: Effects Of Aat In Cell and Solid Organ Transplantationmentioning

confidence: 78%

“…Marcondes et al reported that AAT alters the cellular redox state and improves mitochondrial membrane potential while also increasing expression of antioxidant enzymes such as heme oxygenase 1 (Figure 1). 4, 5, 6, 7 Oxidative stress is important in inflammation and IRI, so these activities may contribute to the ability of AAT to promote cell and tissue survival and modulate inflammatory damage 10, 11, 13, 14, 15, 16, 17, 18, 19, 20. Because different types of lymphocytes, and cells in different activation states, differ in dependence on glycolysis vs oxidative phosphorylation, modulation of mitochondrial function may influence the balance between sensitization and tolerance 6…”

Section: Novel Functions Of Aatmentioning

confidence: 99%

“…AAT has been shown to inhibit apoptosis in multiple in vitro and in vivo models 10, 11, 13, 14, 15, 16, 17, 18, 19, 20. Increased cell survival may result not only from stabilization of mitochondrial membranes, but also likely involves direct inhibition of caspases (Figure 1).…”

Section: Novel Functions Of Aatmentioning

confidence: 99%

“…Increased cell survival may result not only from stabilization of mitochondrial membranes, but also likely involves direct inhibition of caspases (Figure 1). 4, 5, 6, 7, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20 The molecular mechanism(s) of this inhibition have not been elucidated; caspases are cysteine proteases, while elastase and other canonical targets of AAT depend on serine. However, immunofluorescence studies have shown colocalization of AAT and activated caspase 3 in apoptotic but not in viable cells 11.…”

Section: Novel Functions Of Aatmentioning

confidence: 99%

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Alpha-1-antitrypsin in cell and organ transplantation

Berger

Liu

Uknis

et al. 2018

American Journal of Transplantation

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Limited availability of donor organs and risk of ischemia‐reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha‐1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor that limits inflammatory tissue damage. Purified plasma–derived AAT has been well tolerated in more than 30 years of use to prevent emphysema in AAT‐deficient individuals. Accumulating evidence suggests that AAT has additional anti‐inflammatory and tissue‐protective effects including improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting nuclear factor kappa B activation, modulating pro‐ vs anti‐inflammatory cytokine balance, and promoting immunologic tolerance. Cell culture and animal studies have shown that AAT limits tissue injury and promotes cell and tissue survival. AAT can promote tolerance in animal models by downregulating early inflammation and favoring induction and stabilization of regulatory T cells. The diverse intracellular and immune‐modulatory effects of AAT and its well‐established tolerability in patients suggest that it might be useful in transplantation. Clinical trials, planned and/or in progress, should help determine whether the promise of the animal and cellular studies will be fulfilled by improving outcomes in human organ transplantation.

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NADPH oxidase derived reactive oxygen species are involved in human neutrophil IL‐1β secretion but not in inflammasome activation

et al. 2013

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Neutrophils are essential players in acute inflammatory responses. Upon stimulation, neutrophils activate NADPH oxidase, generating an array of reactive oxygen species (ROS).Interleukin-1 beta (IL-1β) is a major proinflammatory cytokine synthesized as a precursor that has to be proteolytically processed to become biologically active. The role of ROS in IL-1β processing is still controversial and has not been previously studied in neutrophils. We report here that IL-1β processing in human neutrophils is dependent on caspase-1 and on the serine proteases elastase and/or proteinase 3. NADPH oxidase deficient neutrophils activated caspase-1 and did not exhibit differences in NALP3 expression, indicating that ROS are neither required for inflammasome activation nor for its priming, as has been reported for macrophages. Strikingly, ROS exerted opposite effects on the processing and secretion of IL-1β; whereas ROS negatively controlled caspase-1 activity, as reported in mononuclear phagocytes, ROS were found to be necessary for the exportation of mature IL-1β out of the cell, a role never previously described. The complex ROS-mediated regulation of neutrophil IL-1β secretion might constitute a physiological mechanism to control IL-1β-dependent inflammatory processes where neutrophils play a crucial role.Keywords: Caspase-1 r IL-1β r NADPH-oxidase r Neutrophil r Reactive oxygen species Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNeutrophils represent the first line of defense against bacterial and fungal infections. Their pivotal role is highlighted by recurCorrespondence: Dr. Analía S. Trevani e-mail: analiatrevani@yahoo.com.ar rent infections in individuals suffering from neutrophil functional disorders or neutropenia [1]. Neutrophils kill microbes by the release of destructive molecules such as proteases and highly reactive oxygen species (ROS), and can also produce a variety of proteins, including cytokines, chemotactic molecules, and other mediators that are involved in their effector functions [2]. However, the microbicidal effectiveness of neutrophils is sometimes obscured by the damage suffered by adjacent healthy tissues; this is a price that has to be paid to contain potentially C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 3324-3335 Innate Immunity 3325 life-threatening situations [3]. Although infections are the major triggers of neutrophil recruitment, many different sterile stimuli, including mechanical trauma, ischemia, toxins, minerals, crystals, and chemicals also lead to neutrophil accumulation in the tissues. In these situations, neutrophils may contribute to inflict collateral damage on otherwise healthy cells [3]. Interleukin-1 beta (IL-1β) is a key cytokine involved in the development of neutrophilic inflammation induced either by microbial or sterile inflammatory stimuli. It is a potent multifunctional proinflammatory cytokine, whose activity is controlled at the le...

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Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia–reperfusion injury

Cited by 130 publications

References 28 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

Alpha-1-antitrypsin in cell and organ transplantation

NADPH oxidase derived reactive oxygen species are involved in human neutrophil IL‐1β secretion but not in inflammasome activation

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