Cholesterol rich lipid raft microdomains are gateway for acute phase protein, SERPINA1

Subramaniyam, Devipriya; Zhou, Huiping; Liang, Min; Welte, Tobias; Mahadeva, Ravi; Janciauskiene, Sabina

doi:10.1016/j.biocel.2010.06.009

Cited by 34 publications

(33 citation statements)

References 43 publications

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“…studies, however, suggest that PR3 has a greater role than NE in IL-1β processing and secretion. (3) PR3 is localized in the same lipid raft domains (75,76) as A1AT (5,20) and LA (77). Bilayer-bound PR3 has a reduced catalytic efficiency, whereas its inhibition by A1AT is more important than that observed for the soluble form of the enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…(18) Recent studies support the concept that some of the pleiotropic activities of A1AT are linked to the specific molecular form of the protein. For example, biological activities of A1AT can be modified due to interactions with lipid moieties, in which A1AT was found in association with cell membrane lipid rafts (19,20) and was detected in complexes with low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs). (21,22) The binding of A1AT to HDL augments its protective effect in a mouse model of elastase-induced pulmonary emphysema.…”

Section: Caspase-1 Inhibition Assaymentioning

confidence: 99%

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α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

Aggarwal

Korenbaum

Mahadeva

et al. 2016

Mol Med

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Section: Resultsmentioning

confidence: 99%

Section: Caspase-1 Inhibition Assaymentioning

confidence: 99%

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

Aggarwal

Korenbaum

Mahadeva

et al. 2016

Mol Med

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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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“…Several studies have shown that calpain may be activated in the cytosol and subsequently translocated to the membrane after interaction with phospholipids (44)(45)(46)(47). Because AAT is shown to be localized in lipid rafts (20,48) and AAT increases cellular lipid content, it is plausible that the transient elevation of cytoplasmic Ca 2+ and lipid redistribution, as induced by exogenous AAT, is required for the calpain I translocation to the membranes, where it is ultimately inhibited by AAT. Interestingly, we observed that AAT does not inhibit calpain I when added to neutrophil lysates and that both AAT and calpain are localized in the neutrophil membrane fractions (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Acute-Phase Protein α1-Antitrypsin Inhibits Neutrophil Calpain I and Induces Random Migration

Al-Omari

Korenbaum

Ballmaier

et al. 2011

Mol Med

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A rapid recruitment of neutrophils to sites of injury or infection is a hallmark of the inflammatory response and is required for effective host defense against pathogenic stimuli. However, neutrophil-mediated inflammation can also lead to chronic tissue destruction; therefore, a better understanding of the mechanisms underlying neutrophil influx and activation is of critical importance. We have previously shown that the acute phase protein α1-antitrypsin (AAT) inhibits neutrophil chemotaxis. In this study, we examine mechanisms related to the effect of AAT on neutrophil responses. We report a previously unknown function of AAT to inactivate calpain I (μ-calpain) and to induce a rapid cell polarization and random migration. These effects of AAT coincided with a transient rise in intracellular calcium, increase in intracellular lipids, activation of the Rho GTPases, Rac1 and Cdc42, and extracellular signal-regulated kinase (ERK1/2). Furthermore, AAT caused a significant inhibition of nonstimulated as well as formyl-metleu-phe (fMLP)-stimulated neutrophil adhesion to fibronectin, strongly inhibited lipopolysaccharide-induced IL-8 release and slightly delayed neutrophil apoptosis. The results presented here broaden our understanding of the regulation of calpain-related neutrophil functional activities, and provide the impetus for new studies to define the role of AAT and other acute phase proteins in health and disease.

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Cholesterol rich lipid raft microdomains are gateway for acute phase protein, SERPINA1

Cited by 34 publications

References 43 publications

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

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

Acute-Phase Protein α1-Antitrypsin Inhibits Neutrophil Calpain I and Induces Random Migration

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