Succinate enhances mitochondrial metabolism and phagocytosis in human airspace monocytes

Slattery, K.; Newing, A.; McGrath, J.; Sanfeliu, A.; O Gallchobhair, O.; Faherty, L.; McNally, E.; O Connell, F.; Nadarajan, P.; Mitchell, P.; Donnelly, S.; Cloonan, S. M.; Keane, J.; Gleeson, L.

doi:10.1101/2025.06.12.659271

bioRxiv · 10.1101/2025.06.12.659271

Succinate enhances mitochondrial metabolism and phagocytosis in human airspace monocytes

Slattery, K.·Newing, A.·McGrath, J.·Sanfeliu, A.·O Gallchobhair, O.·Faherty, L.·McNally, E.·O Connell, F.·Nadarajan, P.·Mitchell, P.·Donnelly, S.·Cloonan, S. M.·Keane, J.·Gleeson, L.

View original source ↗Export metadata ↓

Abstract

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

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Slattery, K., Newing, A., McGrath, J., Sanfeliu, A., O Gallchobhair, O., Faherty, L., McNally, E., O Connell, F., Nadarajan, P., Mitchell, P., Donnelly, S., Cloonan, S. M., Keane, J., Gleeson, L.. 2025-06-17. Succinate enhances mitochondrial metabolism and phagocytosis in human airspace monocytes. https://doi.org/10.1101/2025.06.12.659271

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Common viral infections seed regionally distinct resident memory T cells in the human CNS

T cells persist in the central nervous system (CNS) and can drive both protection and neurological disease. How these cells are organized in humans and what they recognize is largely unknown. Here, we profiled CD8 T cells across anatomically distinct CNS regions, obtained through on-site autopsies and temporal lobe resection surgeries, using single-cell RNA sequencing, paired T cell receptor sequencing, and DNA-barcoded tetramers. Resident memory T cells (TRM) specific for Epstein-Barr virus, cytomegalovirus, influenza A, and SARS-CoV-2 were identified across CNS compartments. Anatomical location was the strongest correlate of TRM cell state, with leptomeningeal cells adopting a cytokine-poised TRM program, whereas brain TRM cells were transcriptionally restrained. Cells of the same clonotype spanned tissues yet adopted local transcriptional states. Viral specificity added another layer of TRM heterogeneity with GZMK/GZMA-expressing EBV-specific populations and interferon-stimulated gene signatures in SARS-CoV-2 and Influenza A-specific cells. The human CNS thus harbors regionally distinct CD8+ TRM shaped by common viral exposures.

immunology↗

bioRxiv2026

A regulatory T cell signature provides a shared molecular basis for the therapeutic window of opportunity in rheumatic disease

Rheumatic diseases, including rheumatoid arthritis (RA), spondyloarthritis (SpA) and osteoarthritis (OA), show distinct phenotypes yet respond to overlapping therapies, implicating shared immune mechanisms. In the Transimmunom cohort, we profiled peripheral blood from 240 individuals (47 healthy, 44 OA, 91 RA, 58 SpA) across deep immunophenotyping, immunoproteomics and Treg-Teff transcriptomics. Single-layer analyses revealed broader Treg than Teff remodeling, along with a shared pattern of reduced activated Tregs and expanded Helios+ Tregs across all diseases, alongside a decrease in functional Treg subpopulations, including CTLA4+ and CD45RA- Tregs. In RA specifically, LAG3+ Tregs were also expanded. Combining omics layers outperformed single-layer approaches for disease classification. Among individual layers, Treg transcriptomes were most discriminative, and integration uncovered disease-specific programs. Unsupervised clustering identified a cross-disease cluster independent of activity, treatment and age, mapping to early disease (<= years) and dominated by a Treg dysfunction-associated program. These results provide a biological rationale for the therapeutic "window of opportunity" concept and duration-stratified Treg-directed trials.

immunology↗

bioRxiv2026

Inhibitory Fc Receptor sets a time limit on macrophage response to IgG

Antibodies engage both activating Fc Receptors and the inhibitory receptor Fc{gamma}RIIB. Why macrophages need a dedicated inhibitory receptor rather than simply tuning activating receptor signaling is unclear. Using DNA-based chimeric receptors and in silico modeling, we independently controlled activating and inhibitory Fc Receptors. We found that Fc{gamma}RIIB imposed a time limit on macrophage phagocytosis and ERK signaling. The time limit is due to activating Fc Receptors converting PI(4,5)P2 to PI(3,4,5)P3, which is subsequently converted to PI(3,4)P2 by Fc{gamma}RIIB. This leads to a pulse of active signaling, which is sufficient for phagocytosis of small bacteria-sized targets but not phagocytosis of large targets and TNF secretion. Unlike engaging Fc{gamma}RIIB, reducing activating Fc Receptor signaling decreased initiation of phagocytosis, the speed of PI(3,4,5)P3 generation, and the amplitude of ERK signaling. Our results demonstrate that Fc{gamma}RIIB controls the duration of IgG signaling, while the activating Fc Receptors control sensitivity.

immunology↗