TY - JOUR
T1 - Circulating platelet-neutrophil aggregates characterize the development of type 1 diabetes in humans and NOD mice
AU - Popp, Sarah K.
AU - Vecchio, Federica
AU - Brown, Debra J.
AU - Fukuda, Riho
AU - Suzuki, Yuri
AU - Takeda, Yuma
AU - Wakamatsu, Rikako
AU - Sarma, Mahalakshmi A.
AU - Garrett, Jessica
AU - Giovenzana, Anna
AU - Bosi, Emanuele
AU - Lafferty, Antony R.A.
AU - Brown, Karen J.
AU - Gardiner, Elizabeth E.
AU - Coupland, Lucy A.
AU - Thomas, Helen E.
AU - Chong, Beng H.
AU - Parish, Christopher R.
AU - Battaglia, Manuela
AU - Petrelli, Alessandra
AU - Simeonovic, Charmaine J.
N1 - Publisher Copyright:
Copyright: © 2022, Popp et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2022/1/25
Y1 - 2022/1/25
N2 - Platelet-neutrophil aggregates (PNAs) facilitate neutrophil activation and migration and could underpin the recruitment of neutrophils to the pancreas during type 1 diabetes (T1D) pathogenesis. PNAs, measured by flow cytometry, were significantly elevated in the circulation of autoantibody-positive (Aab+) children and new-onset T1D children, as well as in pre-T1D (at 4 weeks and 10–12 weeks) and T1D-onset NOD mice, compared with relevant controls, and PNAs were characterized by activated P-selectin+ platelets. PNAs were similarly increased in pre-T1D and T1D-onset NOD isolated islets/insulitis, and immunofluorescence staining revealed increased islet-associated neutrophil extracellular trap (NET) products (myeloperoxidase [MPO] and citrullinated histones [CitH3]) in NOD pancreata. In vitro, cell-free histones and NETs induced islet cell damage, which was prevented by the small polyanionic drug methyl cellobiose sulfate (mCBS) that binds to histones and neutralizes their pathological effects. Elevated circulating PNAs could, therefore, act as an innate immune and pathogenic biomarker of T1D autoimmunity. Platelet hyperreactivity within PNAs appears to represent a previously unrecognized hematological abnormality that precedes T1D onset. In summary, PNAs could contribute to the pathogenesis of T1D and potentially function as a pre-T1D diagnostic.
AB - Platelet-neutrophil aggregates (PNAs) facilitate neutrophil activation and migration and could underpin the recruitment of neutrophils to the pancreas during type 1 diabetes (T1D) pathogenesis. PNAs, measured by flow cytometry, were significantly elevated in the circulation of autoantibody-positive (Aab+) children and new-onset T1D children, as well as in pre-T1D (at 4 weeks and 10–12 weeks) and T1D-onset NOD mice, compared with relevant controls, and PNAs were characterized by activated P-selectin+ platelets. PNAs were similarly increased in pre-T1D and T1D-onset NOD isolated islets/insulitis, and immunofluorescence staining revealed increased islet-associated neutrophil extracellular trap (NET) products (myeloperoxidase [MPO] and citrullinated histones [CitH3]) in NOD pancreata. In vitro, cell-free histones and NETs induced islet cell damage, which was prevented by the small polyanionic drug methyl cellobiose sulfate (mCBS) that binds to histones and neutralizes their pathological effects. Elevated circulating PNAs could, therefore, act as an innate immune and pathogenic biomarker of T1D autoimmunity. Platelet hyperreactivity within PNAs appears to represent a previously unrecognized hematological abnormality that precedes T1D onset. In summary, PNAs could contribute to the pathogenesis of T1D and potentially function as a pre-T1D diagnostic.
UR - http://www.scopus.com/inward/record.url?scp=85123628260&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.153993
DO - 10.1172/jci.insight.153993
M3 - Article
SN - 2379-3708
VL - 7
JO - JCI insight
JF - JCI insight
IS - 2
M1 - e153993
ER -