Neutrophil reprogramming underlie vasculopathy and lung disease in systemic sclerosis

Apr 4, 2026Cell death & disease

Changes in immune cells linked to blood vessel and lung problems in systemic sclerosis

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Abstract

Neutrophils in systemic sclerosis (SSc) showed substantial activation, indicated by elevated plasma levels of Neutrophil Extracellular Trap (NET) byproducts and upregulated TIE2 expression.

In SSc patients, neutrophils displayed significant metabolic reprogramming, characterized by increased autophagy to meet enhanced energy demands.
Neutrophils from systemic lupus erythematosus (SLE) patients exhibited minimal autophagy and lacked TIE2 expression.
Reprogramming of neutrophils in SSc correlated with plasma levels of HMGB1EVs.
Extracellular vesicles from SSc patients adhered to neutrophils in mice, inducing autophagy and TIE2 expression, and promoting lung inflammation and fibrosis.
Effects observed in SSc neutrophils were inhibited by HMGB1 inhibitors and required the HMGB1 receptor, RAGE.
Neutrophil-targeting with liposome-encapsulated clodronate prevented the observed pathological effects.

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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 HMGB1EVs. 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 HMGB1EVs, 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. + +

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Neutrophil reprogramming underlie vasculopathy and lung disease in systemic sclerosis

Abstract

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