De novo COVID-19-associated insulin resistance drives dysregulated neutrophil extracellular trap formation (NETosis) four months after infection

BackgroundGlucose metabolism disorders (GMDs) are established risk factors for severe COVID-19, but increasing evidence indicates that they may also develop de novo after SARS-CoV-2 infection. Neutrophil extracellular trap formation (NETosis) plays a central role in immunothrombosis, and because neutrophils rely predominantly on glycolysis, they are particularly sensitive to systemic metabolic disturbances. However, the impact of post-COVID-19 GMDs on NETosis remains poorly understood. This study aimed to characterize the emergence of GMDs after COVID-19 and to determine their effect on neutrophil NETosis.MethodsSixty COVID-19 patients were stratified according to the presence or absence of GMDs before infection and at four months post-infection. Demographic, clinical, metabolic, and inflammatory parameters were assessed. Vital NETosis was quantified by flow cytometry. In addition, the capacity of patient plasma to induce NETosis was evaluated using live-cell imaging of healthy neutrophils as biosensors.ResultsAmong patients without pre-existing GMDs, 24 of 36 developed insulin resistance (IR) four months after COVID-19. Neutrophils from these patients exhibited increased basal NETosis but showed impaired NETosis in response to TLR7/8 agonists, key sensors of viral single-stranded RNA, compared with control groups. In contrast, NETosis responses to IL-6 and TNF-α were preserved, excluding an intrinsic neutrophil defect. Plasma from IR patients significantly enhanced NETosis, and in vitro experiments demonstrated that insulin enhances NETosis independently of glucose concentrations.DiscussionDe novo IR following COVID-19 dysregulates NETosis primarily through an insulin-enhancing effect. Post-viral control of glucose metabolism disorders may be critical to limit pathological NETosis and its thrombo-inflammatory consequences.