Biology subjects

Murphy, F. K.

Publications and source records attributed to Murphy, F. K..

3 recordsLinked to original sources

bioRxiv2026

SLE Monocyte Subsets Are Pro-Inflammatory and Display Dysregulated Metabolism in Response to Bacterial Stimuli

Systemic lupus erythematosus (SLE) is associated with infection susceptibility and altered innate immune function. Monocyte metabolism is linked to appropriate cytokine release and bacterial containment. We investigated cytokine production and metabolic programming in the monocyte population from SLE patients and healthy controls following lipopolysaccharide (LPS) stimulation. SLE monocytes displayed increased IL-10, TNF, and IL-8 production, with impaired IL-1{beta} induction. Metabolic profiling revealed altered substrate use, with increased glucose dependence and reduced fatty acid and amino acid oxidation after LPS stimulation. SLE patients exhibited reduced numbers of classical monocytes, expansion of intermediate monocytes, and dysregulated subset-specific metabolic reprogramming in response to LPS. This descriptive study provides a cornerstone for (i) understanding infection susceptibility in SLE, (ii) subset-resolved immunometabolic profiling as a tool in autoimmunity, and (iii) developing future metabolic-targeted therapeutic strategies HighlightsO_LIDescriptive mapping shows SLE monocytes are proinflammatory with glucose dependence after LPS C_LIO_LIClassical and intermediate SLE subsets show divergent baseline metabolic preferences versus healthy C_LIO_LISLE subsets display aberrant LPS responses, i.e.. increased glucose and reduced fatty acid oxidation C_LIO_LIThis study provides a cornerstone for subset-resolved immunometabolism in infection susceptibility. C_LI

immunology↗

bioRxiv2026

Neutrophil subsets in SLE exhibit increased glycolysis that correlates with disease activity

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.

immunology↗

bioRxiv2025

Sex-Specific Metabolic Programming in Human Neutrophil Subsets

BackgroundSex differences in immune responses are well-documented, with females exhibiting more robust immunity against infections but higher susceptibility to autoimmune diseases, while males often demonstrate more severe inflammatory pathology. Neutrophils which are key players in the innate immune response, display sex-based functional differences, but whether these extend to metabolic programming, particularly in low-density neutrophils (LDNs), remains unknown. MethodsWe isolated LDNs and normal-density neutrophils (NDNs) from healthy human donors using density gradient centrifugation and negative selection. Cellular metabolism was assessed via Seahorse XF analysis (measuring oxygen consumption rate, OCR, and extracellular acidification rate, ECAR), alongside flow cytometry for maturity markers (CD16hi/lo). ResultsMale LDNs exhibited significantly higher basal OCR and ATP production than female LDNs, while no sex differences were observed in NDNs. Strikingly, male LDNs had higher OCR and glycolysis than their matched NDNs, whereas female NDNs were more oxidative than their LDNs. These metabolic differences were independent of neutrophil maturity, as CD16hi frequencies did not differ between subsets or sexes. ConclusionsOur study reveals, for the first time, subset-specific sexual dimorphism in neutrophil metabolism whereby male LDNs adopt a hypermetabolic (oxidative/glycolytic) phenotype, while female NDNs retain higher oxidative capacity. This reprogramming occurs independently of developmental stage, suggesting sex hormones or epigenetic regulation may drive these differences. These findings provide a metabolic basis for sex-biased immune responses and highlight the need for sex-stratified approaches in neutrophil-targeted therapies. Plain English SummaryMen and women fight infections differently, and our study could reveal why--their immune cells produce energy in distinct ways. We examined two types of neutrophils (infection-fighting cells), normal cells (NDNs) and low-density cells (LDNs) found in inflammation. Using advanced metabolic measurements, we discovered that mens LDNs use more oxygen and generate more energy than womens. Surprisingly, while mens LDNs were more active than their normal neutrophils, women showed the opposite--their normal neutrophils were more energetic than their LDNs. These differences werent due to cell maturity, suggesting biological distinctions between sexes. This may help explain why men often have worse outcomes in diseases like sepsis (where oxygen-driven inflammation dominates), while women are more prone to autoimmune diseases like lupus. Our findings could lead to better sex-specific treatments by dampening overactive immune responses in men or adjusting metabolism in women to prevent autoimmune flares. This research highlights why medical studies must consider sex differences, as one-size-fits-all treatments may miss key biological variations. HighlightsO_LICD16hi frequencies show no sex differences, however female (but not male) NDNs contain significantly more mature CD15+ CD16hi cells than their LDNs, revealing female-specific maturation differences between subsets. C_LIO_LIFirst report of sex-specific metabolic differences in LDNs where males exhibit significantly higher basal respiration and ATP production than female LDNs. C_LIO_LIMale LDNs show higher OCR than matched NDNs, while female NDNs are more oxidative than their LDNs. C_LI

immunology↗