Studying the metabolism and function of myeloid dendritic cells and neutrophils in distinct tissues in health and aging

Projektinformationen

MyTissue

ID Finanzhilfevereinbarung: 101117470

DOI

10.3030/101117470

EK-Unterschriftsdatum 27 September 2023

Startdatum 1 Januar 2024

Enddatum 31 Dezember 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 499 500,00

EU-Beitrag

€ 1 499 500,00

Koordiniert durch

FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Spain

Periodic Reporting for period 1 - MyTissue (Studying the metabolism and function of myeloid dendritic cells and neutrophils in distinct tissues in health and aging)

Berichtszeitraum: 2024-01-01 bis 2026-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Myeloid cells, such as dendritic cells (DCs) and neutrophils, reside in various organs to respond to insults and are key to control immunity and inflammation. However, their aberrant activities in the elderly can cause immunosenecence and inflammaging. Different tissues comprise highly distinct milieus that impose context-dependent biochemical challenges on their resident cells, which further change when tissues age. Yet, it is not known how DCs and neutrophils survive in their different homing organs and maintain their functionality.
I hypothesize that DCs and neutrophils have to adjust their metabolism to the distinct environments of their tissues of residence. This is important, because metabolic changes upon stimulation were shown to affect the functions of those cells in vitro. Given their power to orchestrate immune responses, it is now vital to reveal the precise metabolic adaptions of DCs and neutrophils to their distinct homing organs and to determine how that affects their activities. This pioneering knowledge will expose organ-dependent metabolic vulnerabilities of DCs and neutrophils to uphold their homeostatic and immune functions, which I envisage to cause their dysfunction in aging. I will uncover the metabolic adaptions of DCs and neutrophils to >10 healthy and aged tissues using independent innovative approaches and adapted cutting-edge techniques. I will reveal the relevance of such tissue-dependent metabolic adjustments for their presence and functions in organs, and dissect the underlying molecular mechanisms. I will expose the tissue-specificity of DC and neutrophil dysfunction in aging and the role of their metabolism.
The discovery of tissue-dependent metabolic adaptions by DCs and neutrophils that impact their functions will transform translational immunology research to integrate the tissue-context and reveal novel organ-specific therapeutic strategies to combat immune dysfunction in aging and beyond.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

We have revealed alterations of immune and metabolic gene expression of conventional dendritic cells type 1 and 2 (cDC1s and cDC2s) as well as neutrophils across several tissues in mice, which we partially validated using flow cytometry and metabolomics. We also profiled cDC1s and cDC2s across tissues of aged mice and the analysis of their transcriptome is ongoing. Additionally, we optimized multiplex immunofluorescence stainings for dendritic cells in human tissues and are currently combining them with antibodies detecting metabolic proteins.
Moreover, we generated and preliminary characterized genetically modified mice that harbor dendritic cells with impairments in specific metabolic pathways. Interestingly, we observed a tissue-dependent decline and functional alterations of those metabolically dysfunctional cDC1s and cDC2s. Currently, we are undertaking in-depth transcriptomic and metabolomic analyses of those cells.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

We have generated novel omics datasets of metabolically-impaired and aged dendritic cells across mouse tissues and identified previously not-appreciated tissue-specific vulnerabilities of those cells. Currently, we are investigating the underlying molecular mechanisms, which will likely reveal potential targets to modulate immunity locally, without systemic side effects.