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Take-home: Oxygen sensing splits macrophage identity: 👉 HIF-1α → glycolysis & immature state 👉 HIF-2α → lipid metabolism & surfactant clearance Together, they define maturation, self-renewal, and function OPEN ACCESS:🔗 doi.org/10.1016/j.ce...

Critical functional output: 👉 HIF-2α selectively blocks surfactant clearance • Impaired lipid oxidation • Failure to resolve surfactant in PAP model ✅ Removing HIF-2α restores function 👉 Direct link to lung disease

In vivo competition reveals a key hierarchy: 👉 HIF signaling reduces fitness in the alveolar niche • VHL-deficient AMs are outcompeted • HIF-1α plays a stronger role in niche repopulation defects 👉 Not just phenotype—evolutionary fitness in tissue

Functional consequences on macrophage biology: ❌ Both HIF-1α and HIF-2α impair self-renewal ↓ Ki67, ↓ proliferation BUT: 👉 Full rescue requires removing both 👉 Metabolism and stemness are tightly coupled

But HIF-2α does something very different: 👉 It controls lipid metabolism • Disrupts fatty acid oxidation • Alters macrophage identity genes • Key regulator of lipid-handling programs 👉 Two HIFs → two metabolic axes

Metabolic divergence: 🔥 HIF-1α drives glycolysis • Upregulation of glycolytic genes • ↑ ECAR, ↓ oxidative metabolism • Maintains an immature metabolic program 👉 A Warburg-like state in tissue-resident macrophages

First key point: 👉 HIF activity prevents proper macrophage maturation Deleting VHL → stabilizes HIFs → immature AM phenotype Only removing BOTH HIF-1α + HIF-2α fully restores identity 👉 HIF signaling is the dominant driver downstream of VHL

Waggoner Lab @labwaggoner.bsky.social · 28/05/2026

How does oxygen sensing shape #alveolar #macrophage (AM) identity? Our new @cp-cellreports.bsky.social: HIF-1α and HIF-2α play distinct, non-redundant roles in AM maturation & function A #metabolic split that defines macrophage biology in the lung. 🔗 doi.org/10.1016/j.ce... #CNIC #immunosky

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Reposted by David Sancho

HIF-1α and HIF-2α differentially regulate alveolar macrophage maturation and function @cp-cellreports.bsky.social www.cell.com/cell-reports... @sancholab.bsky.social

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Thanks to your wonderful collaboration and support, Patricia!!! 🫂

📌 Take-home: Mitochondrial complex I → redox control → antigen cross-presentation by DCs → CD8⁺ immunity FREE LINK (for 2000 downloads, PLEASE only use if you have no institutional access, pls): www.science.org/eprint/MTXDH... Led by Sofía & Elena & Michel @CNIC_cardio @sinaiimmuno.bsky.social

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Causality: 🔥 Restoring NAD⁺/NADH balance rescues cross-presentation using: ✅ Nicotinamide riboside ✅ α-ketobutyrate ✅ NDI1 expression 👉 Redox balance—not ATP alone—is the key driver

🧪 Mechanistically, CI dysfunction reshapes metabolism: ❌ ↓ Neutral lipid accumulation ❌ ↓ Lipid peroxidation ❌ Reductive stress (↑ NADH) 👉 These processes are essential for efficient cross-presentation

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In vivo, this matters: 🎯 DC-specific CI deficiency → ❌ Reduced CD8⁺ T cell priming ❌ Impaired antiviral responses ❌ Loss of anti-tumor immunity WT cDC1 vaccines protect in #cancer #immunotherapy CI-deficient cDC1s fail

The key defect: ⚠️ Endosomal antigen escape is impaired → Antigens cannot efficiently reach the cytosol → Cross-presentation is compromised ✅ Direct presentation remains intact 👉 CI selectively controls cross-presentation

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What happens if CI is impaired? 🧬 Using NDUFS4/NDUFS2 deficiency: ❌ mild reduction in mitochondrial respiration, no compensatory glycolysis ❌ ↓ ATP ❌ ↓ NAD⁺/NADH ratio (redox imbalance) BUT: ✅ Normal activation ✅ Normal antigen uptake 👉 Not a general defect—something very specific

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We show that cDC1s—but not cDC2s—boost #mitochondrial CI activity upon activation CI activity → ↑ NAD⁺/NADH ratio Required for optimal DC function This highlights subset-specific metabolic wiring

Waggoner Lab @labwaggoner.bsky.social · 22/05/2026

Does mitochondrial respiration in DCs just “fuel” activation? In our new @ScienceImmunology study, we show that #mitochondrial Complex I is a selective checkpoint for #antigen #cross-presentation in #DCs, especially #cDC1s www.science.org/doi/10.1126/... At: CNIC_CARDIO @inmunosky

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Reposted by David Sancho

Mitochondrial complex I dysfunction in dendritic cells disrupts NAD+/NADH redox balance and impairs antigen cross-presentation @sciimmunology.bsky.social @sancholab.bsky.social www.science.org/doi/10.1126/...

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David Sancho @sancholab.bsky.social · 19/04/2026

Thanks, Esteban! Wonderful collaboration with you and Pep!!! 🫂🫂🫂

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Reposted by David Sancho

Esteban Ballestar @eballestar.bsky.social · 18/04/2026

Wonderful work, David! The concept that ETC flux—not ATP—licenses cDC1 immunogenicity through /metabolite control of DNA methylation is conceptually beautiful. Congrats to Ignacio, Stefanie and the whole team! Thanks for giving us the chance to learn throught this collaboration!

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📌 Take home: An active mitochondrial ETC keeps cDC1s poised for rapid immunogenic responses by tuning redox & metabolite balance controlling DNA methylation—independently of ATP.

🎯 mitochondria-driven metabolite balance controls DC function. ETC impaired cDC1s fail to prime T cells and show reduced anti tumor immunity in vaccination and melanoma models. But AOX rescues this, linking DC mitochondrial metabolism → epigenetics → anti cancer immunity.

🛠️ Restoring electron flow without ATP production (via alternative oxidase, AOX) rescues: ✅ metabolite balance ✅ DNA methylation ✅ cDC1 activation & T cell priming Proof that ETC flux—not energy—licenses immunogenicity.

💡 Loss of ETC function alters key #metabolites: • ↓ NAD⁺/NADH • ↑ 2 hydroxyglutarate • ↑ succinate These changes impair α KG–dependent enzymes (incl. TET2), coupling mitochondrial metabolism to the #epigenetic poising of cDC1s.

🧬 Mechanism: ETC impairment skews DNA methylation in cDC1s. We see hypermethylation at PU.1 and AP 1 binding regions, preventing the rapid induction of immediate early immunogenic genes upon activation.

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⚠️ Cause: this is NOT about ATP. Despite ETC disruption, ATP levels, MMP & ROS remain largely intact. Instead, cDC1 dysfunction emerges from disturbed electron flow, #redox & #metabolite balance. #Mitochondria as signaling hubs regulating #redox & #metabolites, not just batteries.

🔬 We find that cDC1s, but far less cDC2s, rely on intact ETC/OXPHOS to respond rapidly to immunogenic stimuli. ETC impairment selectively blunts cDC1 activation, costimulation, migration and T cell priming capacity linked to decreased immunogenic response & anti#tumor immunity.

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Samarth Hegde @samhegde.bsky.social · 26/02/2026

🤔Do you think that OXPHOS in DCs = tolerance? In our new @cp-cellmetabolism.bsky.social #cnic_cardio & @irbbarcelona.org, we show that active #mitochondrial ETC primes cDC1s for immunogenicity, not tolerance. Life (& #immunometabolism) is not simple ⚡️ OPEN: www.cell.com/cell-metabol... #immunoSky

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Reposted by David Sancho

Always a mind-blowing talk from @sancholab.bsky.social who showed, alongside cool data on macs, that cIII inhibition in cDC1 has functional consequence on anti-tumor immunity > mitochondrial ETC disruption impact on histone demethylase and alter PU.1 pioneer activity. Everything linked !

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#PhD in #immunometabolism on fatty acid oxidation in #macrophage function. MSCA-DN: unimedizin-mainz.de/unlimited-ms... For our DC8 position apply in parallel in 2 sites: 1. unimedizin-mainz.de/unlimited-ms... 2. cnic.es/en/convocato... (DC8: NOT resident in Spain >12m in last 3 years) #immunosky

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Great opportunity for a #PhD on how lipid #metabolism regulates immune cell function in diseases such as cancer and autoimmunity. Train in immunology, bioIT, & metabolism. Apply in parallel in: 1. UNLIMITED: www.unimedizin-mainz.de/unlimited-ms... 2. Local partner site that you choose. #immunosky

The UNLIMITED consortium consists of the following partners:
• University Medical Center of Mainz, Germany (Positions #3, #6, #15)
• Carlos III National Cardiovascular Research Centre, Spain (Positions #8)
• Technical University of Braunschweig, Germany (Positions #9)
• Leiden University Medical Centre, Netherlands (Position #12)
• Amsterdam Umc Foundation, Netherlands (Position #2)
• University of Milan, Italy (Position #7)
• University of Padua, Italy (Positions #4)
• The Provost, Fellows, Foundation Scholars & The Other Members of Board, of The College of The Holy & Undivided Trinity, Ireland (Position #11)
• National Centre for Scientific Research CNRS, France (Position #1)
• University of Cologne, Germany (Position #13)
• Luxembourg Institute of Health, Luxembourg (Position #14)
• Medical University of Vienna, Austria (Position #10)
• Vugene UAB, Lithuania (Position #5)

Visit https://www.unimedizin-mainz.de/unlimited-msca/consortium.html for all the information and application.
Applications must be done in parallel to local positions of each partner that you choose.

Available Positions and Research Topics
The UNLIMITED network offers 15 Doctoral Candidate positions across four themes:
(1) development of innovative tools for single-cell and spatial analysis of lipid immunometabolism (Subprojects 1–5);
(2) molecular pathways linking lipid metabolism to immune activation and differentiation (Subprojects 6–10);
(3) tissue-specific and systemic metabolic regulation of immune function (Subprojects 11–13);
(4) discovery of therapeutic targets within lipid metabolism (Subprojects 14–15).
Collectively, the UNLIMITED network will unravel the lipid–immune interface to generate mechanistic insights that guide the development of precision immunotherapy. Each researcher will receive interdisciplinary, intersectoral training across academia and industry, integrating advanced technologies with transferable and entrepreneurial skills.

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The take home mechanism: An IFN I→ISG15→ATP↑ & MMP↓ pathway enhances efferocytosis, while OMA1 driven fission & reduced ER–mito Ca²⁺ signaling lead to impaired H3K9 histone acetylation that limits ISG amplification—a built in resolve without overreacting program in macrophages. #immunosky

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Physiological balance in infection. In a #vaccinia model, ISG15 or OMA1 deficiency leads to lower viral titers by day 7 (more ISGs), but also shows impaired #apoptotic cell clearance (more tissue damage), illustrating the trade off the axis manages during #resolution. #immunosky

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