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

Platelet microparticles from patients with systemic sclerosis prompt endothelial cell activation, neutrophil recruitment, and lung fibrosis. Platelets nurture neutrophil damage: Systemic sclerosis, or scleroderma, is a complicated inflammatory fibrotic disease involving multiple organs. Different immune cells contribute to the pathology of systemic sclerosis. Maugeri et al. investigated mechanisms that could contribute to endothelial damage in patients. They observed that activated platelets from patients produced microparticles that induced neutrophil activation, including autophagy and neutrophil extracellular trap production. These microparticles expressed the damage-associated molecular pattern HMGB1, and accordingly, an HMGB1 inhibitor prevented this neutrophil activiation. Inhibiting microparticles to interrupt this platelet-neutrophil axis may be helpful to prevent endothelial damage, thereby disrupting disease pathogenesis. 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. [ABSTRACT FROM AUTHOR]