Circulating platelet-neutrophil aggregates characterize the development of type 1 diabetes in humans and NOD mice

Popp, Sarah; Vecchio, Federica; Brown, Debra J.; Fukuda, Riho; Suzuki, Yuhko; Takeda, Yuma; Wakamatsu, Rikako; Sarma, Mahalakshmi A.; Garrett, Jessica; Giovenzana, Anna; Bosi, Emanuele; Lafferty, Antony; Brown, Karen J.; Gardiner, Elizabeth E.; Coupland, Lucy A.; Thomas, Helen E.; Chong, Beng H.; Parish, Christopher R.; Battaglia, Manuela; Petrelli, Alessandra; Simeonovic, Charmaine J.

doi:10.1172/jci.insight.153993

Cited by 24 publications

(35 citation statements)

References 88 publications

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“…Neutrophils, the most abundant phagocytic cell in human blood ( 19 ), display heterogeneous functions and flexibility, developing different profiles in response to different disorders, including autoimmune diseases ( 20 ). A role for neutrophils has been consistently shown in human T1D ( 15 – 17 , 21 ). Circulating neutrophil counts are reduced to the lower limits of the normal range in patients with recent-onset T1D; first‐degree relatives of T1D patients with 2 or more autoantibodies (i.e., pre-symptomatic or pre-T1D) also exhibit a lower circulating neutrophil count which parallels the development of beta cell dysfunction ( 16 ).…”

Section: Role For Neutrophils Nets and Pnas In The Development Of T1dmentioning

confidence: 81%

“…Neutrophils from T1D patients are altered in their phenotype and function. Post-T1D onset, they display reduced migration and chemotaxis ( 25 ), paralleling the sharp decline in circulating PNA levels ( 15 ). They also exhibit impaired phagocytic capacity, leading to reduced clearance of bacteria ( 26 ) and to hyperglycemia-dependent increased susceptibility to infections ( 27 ).…”

Section: Role For Neutrophils Nets and Pnas In The Development Of T1dmentioning

confidence: 99%

“…Indeed we have identified neutrophils and decondensed DNA decorated with MPO and citrullinated histones, indicating the presence of pancreas-residing neutrophils releasing NETs, in both pre-T1D and T1D individuals ( 16 , 17 ). Furthermore, we have recently demonstrated that extracellular histones damage human islets in vitro ( 15 ), providing a putative mechanism for neutrophil-mediated islet cell damage. Of note, methyl cellobiose sulfate (mCBS), a small polyanionic drug that neutralizes the high positive charge of histones, prevented islet cell death ( 15 , 36 ).…”

Section: Role For Neutrophils Nets and Pnas In The Development Of T1dmentioning

confidence: 99%

“…Furthermore, we have recently demonstrated that extracellular histones damage human islets in vitro ( 15 ), providing a putative mechanism for neutrophil-mediated islet cell damage. Of note, methyl cellobiose sulfate (mCBS), a small polyanionic drug that neutralizes the high positive charge of histones, prevented islet cell death ( 15 , 36 ). Thus, mCBS could offer potential, in combination with other agents, for delaying T1D progression.…”

Section: Role For Neutrophils Nets and Pnas In The Development Of T1dmentioning

confidence: 99%

“…As a consequence, NET products, e.g., myeloperoxidase or MPO, neutrophil elastase (NE) and citrullinated histones (CitH3), are commonly used as surrogate markers of NETosis and provide a focus for elucidating the function(s) of neutrophils in T1D. Strongly supporting a pathogenic role for neutrophils/NETs in T1D, circulating levels of indirect markers of neutrophil activation (e.g., PNAs) ( 15 ) and NET proteins (e.g., NE) ( 13 ) follow a dynamic pattern throughout T1D development, largely mirroring levels in islets in NOD mice at different stages of disease progression ( 15 ) or negatively correlating with glycemic control/beta cell function in humans ( 13 ). Surprisingly, studies of T1D human pancreas samples have also revealed neutrophil infiltration and NETosis in exocrine pancreatic tissue ( 16 , 17 ), exposing T1D as a complex immune disease of the pancreas which extends beyond autoimmune damage of islet beta cells ( 18 ).…”

Section: Introduction To Nets In T1dmentioning

confidence: 99%

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The Contribution of Neutrophils and NETs to the Development of Type 1 Diabetes

et al. 2022

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Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin-producing beta cells in pancreatic islets. T lymphocytes are the claimed pathogenic effectors but abnormalities of other immune cell types, including neutrophils, also characterize T1D development. During human T1D natural history, neutrophils are reduced in the circulation, while accumulate in the pancreas where release of neutrophil extracellular traps (NETs), or NETosis, is manifest. Recent-onset T1D patients also demonstrate activated circulating neutrophils, associated with a unique neutrophil gene signature. Neutrophils can bind to platelets, leading to the formation of platelet-neutrophil aggregates (PNAs). PNAs increase in the circulation during the development of human T1D and provide a mechanism for neutrophil activation and mobilization/recruitment to the pancreas. In non-obese diabetic or NOD mice, T1D autoimmunity is accompanied by dynamic changes in neutrophil numbers, activation state, PNAs and/or NETosis/NET proteins in the circulation, pancreas and/or islets. Such properties differ between stages of T1D disease and underpin potentially indirect and direct impacts of the innate immune system in T1D pathogenesis. Supporting the potential for a pathogenic role in T1D, NETs and extracellular histones can directly damage isolated islets in vitro, a toxicity that can be prevented by small polyanions. In human T1D, NET-related damage can target the whole pancreas, including both the endocrine and exocrine components, and contribute to beta cell destruction, providing evidence for a neutrophil-associated T1D endotype. Future intervention in T1D could therefore benefit from combined strategies targeting T cells and accessory destructive elements of activated neutrophils.

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Section: Role For Neutrophils Nets and Pnas In The Development Of T1dmentioning

confidence: 81%

Section: Role For Neutrophils Nets and Pnas In The Development Of T1dmentioning

confidence: 99%

Section: Role For Neutrophils Nets and Pnas In The Development Of T1dmentioning

confidence: 99%

Section: Role For Neutrophils Nets and Pnas In The Development Of T1dmentioning

confidence: 99%

Section: Introduction To Nets In T1dmentioning

confidence: 99%

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The Contribution of Neutrophils and NETs to the Development of Type 1 Diabetes

et al. 2022

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Multi‐omics analysis reveals drivers of loss of β‐cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA multicenter study

Armenteros,

Brorsson,

Johansen

et al. 2024

Diabetes Metabolism Res

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AimsHeterogeneity in the rate of β‐cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease‐modifying clinical trials. Integrative analyses of baseline multi‐omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rates of disease progression after type 1 diabetes diagnosis.MethodsWe collected samples in a pan‐European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study, we used Multi‐Omics Factor Analysis to identify molecular signatures correlating with post‐diagnosis decline in β‐cell mass measured as fasting C‐peptide.ResultsTwo molecular signatures were significantly correlated with fasting C‐peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signalling, lymphoid and non‐lymphoid cell interactions and G‐protein coupled receptor signalling events that were inversely associated with a rapid decline in β‐cell function. The second signature was related to translation and viral infection was inversely associated with change in β‐cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid β‐cell decline.ConclusionsFeatures that differ between individuals with slow and rapid decline in β‐cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies as well as offering biomarkers of therapeutic effect.

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A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis

Bellomo,

Patava,

Van Lancker

et al. 2024

Pharmacology Res & Perspec

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Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre‐clinical studies showed benefit with a histone‐neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose‐adjusted, open‐label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady‐state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug‐related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half‐life values ranged from 5 to 7 h. The mean (±SD) terminal half‐life for non‐RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified.

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Circulating platelet-neutrophil aggregates characterize the development of type 1 diabetes in humans and NOD mice

Cited by 24 publications

References 88 publications

The Contribution of Neutrophils and NETs to the Development of Type 1 Diabetes

The Contribution of Neutrophils and NETs to the Development of Type 1 Diabetes

Multi‐omics analysis reveals drivers of loss of β‐cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA multicenter study

A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis

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