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Biology subjects

Slattery, K.

Publications and source records attributed to Slattery, K..

2 recordsLinked to original sources
bioRxiv2025

Succinate enhances mitochondrial metabolism and phagocytosis in human airspace monocytes

Airspace macrophages (AM) are crucial to host defence and to maintenance of lung homeostasis, with smoking drastically compromising these functions. Airspace monocytes, precursors of the differentiated AM, are found in increased numbers in the lungs of smokers yet little is known about their metabolic regulation and function. Here, we develop a click chemistry-based single cell analysis platform to characterise human airspace monocytes and AM ex vivo, identifying distinct metabolic profiles and a key role for oxidative phosphorylation in supporting phagocytic function. While blood and newly recruited CD93+ airspace monocytes show low mitochondrial dependency, AM rely heavily on oxidative phosphorylation. Acute succinate supplementation enhanced mitochondrial metabolism and phagocytosis in monocytes and promoted their differentiation into highly oxidative macrophages with enhanced function. Succinate emerges as a promising candidate to restore lung immune function, particularly in the smokers lung where airspace monocytes are enriched. Overall, we identify mitochondrial metabolism as a key modulator of lung immune function and a target for therapeutic intervention, with potential applications in systemic monocyte-targeted therapies and metabolic preconditioning for adoptive cell therapies. One Sentence Summary: Mitochondrial metabolism regulates phagocytic function in human lung monocytes and macrophages and can be targeted using succinate. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/659271v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@18c8716org.highwire.dtl.DTLVardef@f8f4b8org.highwire.dtl.DTLVardef@8a806forg.highwire.dtl.DTLVardef@f5f8b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗
bioRxiv2019

TGFβ drives mitochondrial dysfunction in peripheral blood NK cells during metastatic breast cancer

Natural Killer (NK) cells provide important protection from cancer and are a key requirement for particular immunotherapies. In activated NK cells, a metabolic response towards increased glycolysis and oxidative phosphorylation is crucial for NK cell effector functions. However, there is accumulating evidence that NK cells become dysfunctional during chronic inflammatory diseases, such as human breast cancer. This dysfunction is apparent in peripheral blood NK cells and can impact on normal NK cell immune responses and their effective targeting during immunotherapy. Herein, we demonstrate that prolonged cytokine stimulation combined with metabolic restriction, through inhibition of mTORC1, is sufficient to induce persistent dysfunction in human NK cells. TGF{beta}, also restricted NK cell metabolism and promoted persistent NK cell dysfunction. NK cells from patients with metastatic breast cancer had profound metabolic defects in glycolysis and mitochondrial function, and clear structural differences in NK cell mitochondrial morphology. Importantly, blocking elevated TGF{beta} improved readouts of metabolism and restored IFN{gamma} production in patient NK cells.

immunology↗