Monocyte NLRP3 inflammasome and interleukin-1 activation modulated by alpha-1 antitrypsin therapy in deficient individuals
THORAX(2024)
Abstract
Introduction Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1 beta secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers. Methods Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1 beta secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors. Results C3d acting via CR3 induces NLRP3 and pro-IL-1 beta production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1 beta secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0 +/- 1.2 mu g/mL vs 1.3 +/- 0.5 mu g/mL respectively, p<0.0001) and IL-1 beta (115.4 +/- 30 pg/mL vs 73.3 +/- 20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation. Discussion These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.
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Key words
alpha1 antitrypsin deficiency,innate immunity,rare lung diseases
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