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Published on: November 30, 2021
NETosis inhibitory activity of LBW newborns' cord blood plasma reverses lupus-associated immunopathology
Hiral Thacker1, Khushbu Priya2, Uma Pandey3
1Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Background:
Pathological NETosis contributes to immune dysregulation and organ damage in systemic lupus erythematosus (SLE), positioning it as a potential therapeutic target. Previous studies have shown suppressed NETosis in term low birth weight (tLBW) newborns. Several NETosis-suppressive molecules, including the α1-antitrypsin-derived C-terminal peptide and CRISPP have been reported in cord blood (CB) plasma and have shown suppressive effects on NET formation. Given the pathogenic role of excessive NETosis in SLE, these observations suggest that LBW newborns' CB plasma (LP) may contain putative NETosis-inhibitory factors with therapeutic potential and support further investigations.
Objectives:
To evaluate the NETosis-inhibitory activity of LP and its effects on lupus-associated pathological features in neutrophils from patients with SLE and in the pristane-induced lupus (PIL) mouse model.
Methods:
Ex vivo effects of LP on NETosis were evaluated using neutrophils from patients with SLE (n=35) and PIL mouse (n=18; n=6/group). NET formation was assessed by extracellular DNA release and expression of key markers, including citrullinated histone H3 (CitH3), neutrophil elastase (NE), and myeloperoxidase (MPO), along with cytoplasmic and mitochondrial ROS production. In vivo efficacy was determined by measuring reduction in NETosis, oxidative stress, anti-dsDNA autoantibody levels, proteinuria, and improvement of tissue oxygenation and vascularization in the heart, liver and kidneys of PIL mice.
Results:
LP significantly reduced NET formation, as evidenced by reduced extracellular DNA release and expression of CitH3 and NE in SLE neutrophils. Extracellular DNA release decreased by 13% and 16.66% along with a reduction in netting neutrophils by 27.4% and 21.12% under basal and LPS-stimulated conditions, respectively. LP also suppressed ROS production in SLE neutrophils. In PIL mice, LP reduced NETosis (30.93%) and oxidative stress (15.34%mitochondrial ROS; 24.28% cytoplasmic ROS) in blood-derived neutrophils, decreased MPO and Sytox Orange signal intensities in the heart, liver, and kidneys. LP further decreased anti-dsDNA autoantibody levels (57.9%) and proteinuria (93.59%), preserved vascular integrity, and improved tissue oxygenation.
Conclusion:
LP exhibits NETosis-inhibitory activity and ameliorates lupus-associated pathology in the PIL mouse and ex vivo SLE neutrophil system. These findings suggest the presence of as-yet-uncharacterized endogenous plasma components that modulate NET formation and support further investigation as potential therapeutics for SLE.
