AI Insight
This study investigated the metabolic characteristics of two neutrophil populations — low-density neutrophils (LDNs) and normal-density neutrophils (NDNs) — isolated from patients with systemic lupus erythematosus (SLE) and healthy controls. Using the Seahorse MitoStress assay, researchers found that both LDN and NDN subsets from SLE patients with active disease (SLEDAI ≥ 4) showed significantly elevated extracellular acidification rates (ECAR), indicating increased reliance on glycolysis. Furthermore, SLE LDNs displayed an immature phenotype and enhanced metabolic flexibility, and pharmacological inhibition of glycolysis altered their inflammatory and maturation-associated surface marker expression, suggesting a direct link between glycolytic metabolism and pathogenic neutrophil behavior in SLE.
Why it matters
These findings position neutrophil immunometabolism — specifically glycolysis — as a potentially actionable therapeutic target in SLE, raising the possibility that metabolic interventions could dampen pro-inflammatory neutrophil activity and reduce disease-associated tissue damage.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by sustained type I interferon signalling and widespread immune dysregulation. Low-density neutrophils (LDNs) are expanded in SLE and display pro-inflammatory and tissue-damaging properties. However, their metabolic phenotype remains poorly defined. Here, we performed a comprehensive metabolic characterisation of circulating LDNs and normal-density neutrophils (NDNs) from patients with SLE and matched healthy individuals (HC). Neutrophil subsets were isolated from peripheral blood of SLE patients and HC donors using a two-step protocol of negative selection and Percoll density centrifugation. Immunophenotyping phenotype was carried out by flow cytometry to assess phenotypic expression of common neutrophil markers CD15, CD16, CD10, CD66b, CD62L, MPO, and IL-1{beta}. Bioenergetic profiling of LDNs and NDNs was performed in situ using the Seahorse MitoStress test to measure oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Metabolic flexibility and phenotypic alterations were assessed in LDNs and NDNs following inhibiting mitochondrial metabolism with oligomycin and glycolysis with 2DG. We found that SLE LDNs exhibit an immature phenotype compared with autologous and healthy NDNs, as determined transcriptionally by C/EBP{varepsilon} and by surface protein expression levels of CD10. Both LDNs and NDNs from SLEDAI[≥]4 patients demonstrated significantly elevated ECAR relative to HC neutrophils. Further, SLE LDNs displayed enhanced metabolic flexibility, with the capacity to switch towards a glycolytic phenotype under metabolic stress conditions. Inhibition of glycolysis altered the inflammatory and maturation-associated phenotype of both SLE neutrophil subsets, indicating a direct link between cellular metabolism and pathogenic neutrophil function. Collectively, these findings identify fundamental metabolic alterations in SLE neutrophil subsets and support neutrophil immunometabolism as a potential therapeutic target in SLE.
Source: Neutrophil subsets in SLE exhibit increased glycolysis that correlates with disease activity