Circulating Truncated Alpha-1 Antitrypsin Glycoprotein in Patient Plasma Retains Anti-Inflammatory Capacity

Abstract

Alpha-1 antitrypsin (AAT) is an acute phase protein that possesses immune regulatory and anti-inflammatory functions independent of anti-protease activity. AAT deficiency (AATD) is associated with early onset emphysema and chronic obstructive pulmonary disease. Of interest are the AATD nonsense mutations (termed Null or Q0) the majority of which arise from premature termination codons (PTC) in the messenger RNA coding-region. We have recently demonstrated that plasma from an AATD patient homozygous for the Null Bolton-allele (Q0bolton) contains AAT protein of truncated size. Although the potential to alleviate the phenotypic consequences of AATD by increasing levels of truncated protein holds therapeutic promise, protein functionality is key. The goal of this study was to evaluate the structural features and anti-inflammatory capacity of Q0bolton-AAT. A low abundance, truncated AAT protein was confirmed in plasma of a Q0bolton- AATD patient and was secreted by patient-derived iPSC-hepatic cells. Functional assays confirmed the ability of purified Q0bolton-AAT protein to bind neutrophil-elastase and to inhibit protease activity. Q0bolton-AAT bound interleukin-8 and leukotriene B4, comparable to control M-AAT, and significantly decreased leukotriene B4 induced neutrophil adhesion (P=0.04). Through a mechanism involving increased mRNA stability (P=0.007), ataluren treatment of HEK-293 significantly increased Q0bolton-AAT mRNA expression (P=0.03) and Q0bolton-AAT truncated protein secretion (P=0.04). Results support the rationale for treatment with pharmacological agents that augment levels of functional Q0bolton-AAT protein, thus offering a potential therapeutic option for AATD patients with rare mutations of similar theratype.

Chronic Periodontitis and Alzheimer Disease: A Putative Link of Serum Proteins Identification by 2D-DIGE Proteomics

“…Approximately 500 protein spots were successfully matched between the two groups on each gel, and 10 proteins that underwent significant changes (nine up-regulated and one down-regulated) were identified ( Table 2). Of the 10 proteins, three have been previously reported to play a positive role in the inflammatory process: Haptoglobin, Alpha-1-antitrypsin, and Complement factor B, which supports our findings (Chou et al, 2012;Ostvik et al, 2014;Yang et al, 2017;Cholette et al, 2018;Balbi et al, 2019;Reeves et al, 2019). It is proposed that inflammation, originated from CP, might add to the inflammatory pool in the serum by contributing several pro-inflammatory mediators, such as C-reactive protein, interleukin (IL)-1, IL-6, and TNF-α, which cause cell apoptosis, tumor genesis, neuro-inflammation, and a systemic immune response (Rapone et al, 2019;Wang et al, 2019).…”

Association between α1‑antitrypsin and acute coronary syndrome

“…It is also a serine protease inhibitor which circulates in healthy individuals and is usually increased in most inflammatory diseases such as ACS (10). The normal AAT plasma level is 1.04 g/l or ~20 µM (11) and this may increase by 3-5-fold when an inflammatory reaction occurs (12).…”

A new electrochemical impedance biosensor based on aromatic thiol for alpha-1 antitrypsin determination

“…This concentration increases normally as manifolds in case of an acute inflammation or post-infection and in a number of conditions, ranging from acute community-acquired pneumonia to post-surgery [7]. However, the decrease in A1AT level in blood is clinically more important, which detected owing to a disorder called alpha-1 antitrypsin deficiency (AATD) caused by mutations in the gene encoding A1AT protein.…”