Immuno-metabolic dysregulation in type 2 diabetes is associated with altered neutrophil functional plasticity, mitochondrial dysfunction, and compromised responses in sepsis.

BACKGROUND: Constitutively activated neutrophil extracellular traps (NETs) have been implicated in the impeded response to infections in Type 2 Diabetes (T2D). However, immuno-metabolic factors contributing to functional plasticity of neutrophils in T2D associated infections are not known. METHODS: Using both human and mice model of sepsis with either diabetic or non-diabetic background, we investigated functionally confined neutrophil subpopulations either executing phagocytosis or NETosis. An integrated analysis of cytokines regulating granulopoiesis, RNAseq of NETs forming neutrophils and metabolomics was performed. Mitochondrial function was assessed via measuring mitochondrial membrane potential, cellular oxygen consumption rate and mitophagy. RESULTS: We identified neutrophil subpopulations either executing phagocytosis or NETosis. Proportions of these functionally restricted neutrophils are significantly altered in T2D and fail to elicit an immune response upon induction of sepsis. Integrated analysis involving cytokines, transcriptome and metabolome data revealed perturbed immunometabolic axis in T2D models majorly effecting mitochondrial metabolism. Molecular dynamic simulations indicate deformed lipid densities and disrupted inner mitochondrial membrane. T2D neutrophils showed decrease in mitochondrial membrane potential, cellular oxygen consumption rate and mitophagy. Arachidonic acid supplementation activated mitochondrial ROS and restored NETs formation in T2D upon sepsis. CONCLUSIONS: In mouse models, along with preliminary findings in human subjects, our study provides novel and correlative insights into the relationship between metabolic changes and neutrophil dysfunction in T2D-associated sepsis, exploring immuno-metabolism as a therapeutic target to improve neutrophil function.