Altered mitochondrial homeostasis in SLE neutrophils promotes aberrant NET release but blunts NETosis during infection.

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a lack of immune tolerance to nuclear antigens leading to systemic inflammation. Patients with SLE are more susceptible to bacterial infections, which is thought to be the result of immunosuppressants used to treat their disease. However, we showed that SLE neutrophils are impaired in their response to bacterial infection. While the unique cell death process resulting in the formation of neutrophil extracellular traps (NET; NETosis) has been attributed to antagonizing SLE pathology, we demonstrated that SLE neutrophils fail to undergo NETosis in response to the bacterial pathogens. Herein, we identified that production of lactate by phylogenetically distinct bacterial pathogens caused increased generation of mitochondrial superoxide and triggered NET release. In contrast, SLE neutrophils displayed an altered metabolic state that rendered them incapable of sensing bacterial lactate. As such, SLE neutrophils failed to undergo NETosis in response to the bacterial pathogen Staphylococcus aureus and underwent aberrant NET release upon stimulation with apoptotic debris. These results indicate that NET formation in response to bacteria may be distinct from pathways promoting heightened NETosis in SLE. Furthermore, deciphering the metabolic disruptions driving inappropriate NET formation in SLE may lead to clinically actionable biomarkers that limit accumulation of nuclear antigens and restores host defense.