A GPVI-platelet-neutrophil-NET axis drives systemic sclerosis

Systemic sclerosis (SSc) is characterized by progressive fibrosis of skin, lung, and other organs and retains among the highest rates of mortality among autoimmune diseases. We identified activation of circulating neutrophils from patients with diffuse SSc, together with concordant transcriptomic evidence of neutrophil activation in blood, skin, and lungs, and in mice with experimental SSc of skin and lung induced by hypochlorous acid or bleomycin. Neutrophil depletion abrogated experimental SSc, while adoptive transfer of SSc neutrophils induced skin and lung fibrosis in healthy mice, identifying neutrophils as both necessary and sufficient for disease. In patients, platelet activation accompanied diffuse SSc, and in mice platelet activation preceded neutrophil activation, suggesting an upstream role. Platelet depletion abrogated both neutrophil activation and tissue fibrosis. SSc platelets conferred upon neutrophils the capacity to induce SSc. This capacity corresponded to enhanced production of neutrophil extracellular traps (NETs); experimental SSc was abrogated in NET-deficient PAD4 ^-/- mice, a resistance bypassed by adoptive transfer of PAD4-suficient SSc neutrophils, confirming NETs as a key effector mechanism of SSc. In turn, platelet activation was mediated via the platelet collagen receptor GPVI, while GPVI deficiency resulted in attenuated platelet and neutrophil activation, fewer circulating NETs, and protection from fibrosis in both murine models of SSc. Together, these findings define a GPVI-platelet-neutrophil-NET axis in SSc and identify a new set of therapeutic targets in this often-refractory condition.