Neutrophils Fuel Effective Immune Responses through Gluconeogenesis and Glycogenesis

Abstract

Summary Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U- 13 C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.

­­­­­­­A type I IFN, prothrombotic hyperinflammatory neutrophil signature is distinct for COVID-19 ARDS­­­

“…It is therefore of interest that in response to IFNα and IFNβ, neutrophils rewire their metabolic programme by reducing their glycolytic potential. Together with an increase in detectable levels of glutamate in neutrophils isolated from patients with COVID-19 ARDS, and existing evidence that neutrophils can undergo gluconeogenesis 54 , this raises the interesting possibility that ARDS neutrophils re-wire their metabolic processes to facilitate ongoing inflammatory responses which may be detrimental to the host. Future work will be required to better understand whether these metabolic changes potentiate anti-viral and pro-inflammatory innate immune responses following viral challenge.…”

Metabolic Pathways Involved in Formation of Spontaneous and Lipopolysaccharide-Induced Neutrophil Extracellular Traps (NETs) Differ in Obesity and Systemic Inflammation

“…These prima facie unexpected results can be explained by the fact that neutrophils of obese mice derive from the inflammatory environment, as obesity is accompanied by low grade inflammation [ 7 ], whereas inflammatory neutrophils accumulate even 10-fold more glycogen than the noninflammatory/quiescent ones [ 87 ]. Thus, neutrophils of HFD mice might were utilizing glycogen for ATP production as inflammatory neutrophils do [ 18 ]. Consistently, inhibition of glycogen breakdown in neutrophils (either LPS-stimulated or nonactivated) reduces their survival in glucose-deprived conditions [ 18 ].…”

“…Thus, neutrophils of HFD mice might were utilizing glycogen for ATP production as inflammatory neutrophils do [ 18 ]. Consistently, inhibition of glycogen breakdown in neutrophils (either LPS-stimulated or nonactivated) reduces their survival in glucose-deprived conditions [ 18 ]. This implies that intracellular glucose stores are essential to meet neutrophil energy demands in conditions where fuels are limited, e.g., inflammation.…”

“…Also, murine neutrophils strongly express GLUT1, although not necessarily GLUT3 and 4 [ 17 ]. Moreover, they tightly regulate glucose utilization via glycogen cycling to match energy requirements to the immediate demands such as those during inflammation [ 18 ]. Additionally, they carry only 5–6 mitochondria on average [ 19 ], thus significantly less than other leukocytes or even granulocytes (e.g., eosinophils have 24–36 mitochondria per cell [ 19 ]) or other cell types (e.g., hepatocytes contain 1000–2000 mitochondria per cell [ 20 ]).…”

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

“…Therefore, USP2 may regulate various cellular functions by modulating energy metabolism. In particular, a number of recent papers demonstrate that energy metabolism states predominantly influence immunological function, suggesting that USP2 controls immune and/or proinflammatory responses of lymphocytes or macrophages by altering cellular metabolism [178][179][180][181][182]. A review of the molecular events involving USP2 may facilitate the characterization of its common functions and enable the understanding of its significance at an individual level.…”