Proyectos - Internacionales - Programas de Investigación e Innovación de la UE

We are investigating how tissue damage and microbial signals lead to mitochondrial reprogramming in dendritic cells (DCs) and macrophages, and how manipulation of mitochondrial metabolism regulates myeloid cell function. This project aims to identify new targets to exploit DCs and macrophages for improved immunotherapy. So far we have: 1. Characterized the metabolic reprogramming after DC stimulation with different stimuli both in mouse and human DCs. 2. We are performing the analysis of how innate sensing connects with mitochondrial adaptations in DCs; 3. We have addressed the effect of drugs targeting mitochondrial biology and now we are analyzing the effect of genetic manipulation of mitochondrial biology on DC function in vitro. 4. We are assessing the functional in vivo effects of targeting mitochondrial biology in DCs in homeostasis and disease.

The project aims 1. the analysis of how sensing of external stimuli by DCs leads to mitochondrial adaptations; 2. The investigation in how mitochondrial metabolism may impact in DC function.

The main results obtained in these aims are:
1. In the current reporting period we have found how macrophage polarization is regulated by Fgr kinase-mediated phosphorylation of mitochondrial CII, which impacts on proinflammatory macrophages in the adipose tissue. Fgr deficiency leads to improved glucose metabolism and leaner mice with reduced liver steatosis (Acín-Pérez et al. Nat Metabolism 2020). In addition, we found that a polybacterial preparation induces metabolic reprogramming and trained immunity, protects against viral infection and enhances vaccine immunogenicity (Brandi et al. 2022. Cell Reports; del Fresno et al. Front. Immunol. 2021).
2. Our novel genetic approaches based on CD11c-selective deletion of key proteins affecting OXPHOS complexes have revealed diverse results depending on the targeted complex. We performed the analysis of CD11c-expressing macrophages. We found that distinct physiological functions direct the metabolic requirements of tissue-resident macrophages. Using the CD11c-Cre driver line, we observed a profound phenotype in some CD11c-expressing macrophage (MF) populations. Using our CD11c∆Tfam mice and Lysozyme M-Cre Tfamf/f (LysM∆Tfam) mice, we found that mitochondrial impairment differentially affects presence and identity of MFs correlating with their expression levels of OXPHOS-related genes. Alveolar macrophages are drastically affected and the oxphos is needed for macrophage lipid handling activity. Macrophages in tissues exposed to lipids in homeostasis are more dependent on oxphos for their metabolism. In addition, proinflammatory macrophages in the adipose tissue are also oxphos-dependent. Due to the lack of this proinflammatory macrophages, LysM∆Tfam mice are leaner and show better glucose metabolism and less liver steatosis than control mice (Wculek et al. submitted).

In relation with the previous mentioned objectives, the progress and expected potential are:
1. We have characterized how innate stimuli lead to distinct metabolic signatures and have described modulatory mechanisms that affect metabolic reprogramming and trained immunity (Saz-Leal et al. Cell Reports. 2018). We found that a polybacterial preparation induces metabolic reprogramming and trained immunity, protects against viral infection and enhances vaccine immunogenicity (Brandi et al. 2022. Cell Reports; del Fresno et al. Front. Immunol. 2021).We are now working on new regulators of trained immunity with particular focus on the role of mitochondrial metabolism.
2. In our biased approach we have established the involvement of the HIF-1 pathway in alveolar macrophage function and the importance of sensing oxygen for terminal differentiation (Izquierdo et al. Cell Reports. 2018). We are also analyzing other sensing pathways that affect DC and macrophage mitochondrial metabolism.
3. We have found a new function in inflammation of DCs (Del Fresno et al. Science. 2018) and a new pathway of sensing microbiota that affects immunity in the gut (Martínez-López et al. Immunity. 2019). This has potential impact as new functional targets that can be affected by the manipulation of mitochondrial metabolism, and we are currently exploring this avenue. In fact, we have recently described that Fgr kinase can modulate mitochondrial complex II activity and macrophage polarization, which affects host metabolism. Fgr promotes proinflammatory macrophage polarization, obesity and metabolic syndrome (Acín-Pérez et al. Nat Metab. 2020).
4. Our work has established that cDC1s can be effectively used for cancer immunotherapy (Wculek et al. JITC. 2019). The potential is to manipulate metabolism in cDC1s to improve cancer immunotherapy.