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Sci Transl Med. 2018 Jul 25;10(451). pii: eaao3089. doi: 10.1126/scitranslmed.aao3089.

Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis.

Author information

1
Università Vita-Salute San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy. maugeri.norma@hsr.it manfredi.angelo@hrs.it.
2
Università Vita-Salute San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy.

Abstract

Endothelial cell damage and platelet activation contribute to sustained vasculopathy, which is a key clinical characteristic of systemic sclerosis (SSc), also known as scleroderma. Microparticles released from activated platelets in the blood of SSc patients (SSc-microparticles) are abundant and express the damage-associated molecular pattern (DAMP) HMGB1. SSc-microparticles interacted with neutrophils in vitro and in immunocompromised mice and promoted neutrophil autophagy, which was characterized by mobilization of their granule content, enhanced proteolytic activity, prolonged survival, and generation of neutrophil extracellular traps (NETs). Neutrophils migrated within the mouse lung, with collagen accumulation in the interstitial space and the release of soluble E-selectin by the vascular endothelium. Microparticle-neutrophil interaction, neutrophil autophagy and survival, and generation of NETs abated in the presence of BoxA, a competitive inhibitor of HMGB1. Consistent with these results, neutrophils in the blood of SSc patients were autophagic and NET by-products were abundant. Our findings implicate neutrophils in SSc vasculopathy and suggest that platelet-derived, microparticle-associated HMGB1 may be a potential indicator of disease and target for novel therapeutics.

Comment in

PMID:
30045975
DOI:
10.1126/scitranslmed.aao3089
[Indexed for MEDLINE]

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