<p>The role of neutrophils in systemic sclerosis (SSc) remains incompletely understood. To address this, blood samples from 39 SSc patients, 39 healthy controls, and 22 systemic lupus erythematosus (SLE) patients were analyzed. Our results indicate that in SSc, neutrophils exhibited substantial activation, evidenced by granule mobilization, elevated plasma levels of Neutrophil Extracellular Trap (NET) byproducts, and upregulated TIE2 expression. In parallel, they underwent metabolic reprogramming, characterized by increased autophagy, likely to support the heightened energy demands of activation. By contrast, neutrophils from SLE patients displayed minimal autophagy, lacked TIE2 expression, and shifted toward low-density granulocytes. Neutrophil reprogramming in SSc correlated with plasma levels of HMGB1⁺ EVs. Mechanistically, EVs purified from the plasma of patients with SSc adhered to neutrophils when injected in immunodeficient NSG mice, inducing autophagy, TIE2 expression, and promoting lung inflammation and fibrosis. These effects were abrogated by HMGB1 inhibitors and required the HMGB1 receptor, RAGE. Recombinant HMGB1 recapitulated EV-induced effects, while neutrophil targeting by liposome-encapsulated clodronate prevented them. In summary, neutrophils in SSc exhibit a dual phenotype of autophagy and activation driven by HMGB1⁺ EVs, representing a pathogenic mechanism with therapeutic potential in SSc. This mechanism operates similarly in male and female mice and is sufficient to induce neutrophil-driven lung injury in vivo.</p>