Do mature neutrophils reactivate mitochondrial metabolism when responding to inflammatory stimuli?

Details

Neutrophils are highly abundant innate immune cells, continually produced from myeloid progenitors in the bone marrow. Once differentiated, they can carry out a range of effector functions critical for host defense. This study aimed to quantitatively understand mitochondrial metabolism during neutrophil differentiation and activation, and to determine how it affects neutrophil functions.

In this laboratory experimental study, the researchers used murine ER-Hoxb8 myeloid progenitor-derived neutrophils and human induced pluripotent stem cell-derived neutrophils as models to examine metabolic remodeling during differentiation. To examine remodeling during activation, they exposed differentiated ER-Hoxb8 neutrophils and primary human neutrophils to various stimuli, including ionomycin, monosodium urate crystals, and phorbol 12-myristate 13-acetate. They characterized cellular metabolism using isotopic tracing, extracellular flux analysis, metabolomics, and fluorescence-lifetime imaging microscopy, revealing dynamic changes in mitochondrial metabolism.

As neutrophils matured, mitochondrial metabolism declined drastically, energy production shifted away from oxidative phosphorylation, and glucose oxidation through the TCA cycle was substantially reduced. Nevertheless, mature neutrophils retained the capacity for mitochondrial metabolism. With certain stimuli, the TCA cycle was rapidly activated.

Mitochondrial pyruvate carrier inhibitors reduced this reactivation of the TCA cycle and inhibited the release of neutrophil extracellular traps. Treatment with these inhibitors also affected neutrophil redox status, migration, and apoptosis, without significantly changing overall bioenergetics.

The researchers concluded that mitochondrial metabolism is dynamically remodeled and plays a significant role in neutrophils. They also identified therapeutic potential for mitochondrial pyruvate carrier inhibitors in a range of conditions in which dysregulated neutrophil responses drive inflammation and contribute to pathology.