Periodic Reporting for period 4 - MITOMAD (Functional characterisation of mitochondrial metabolic adaptations to innate sensing in dendritic cell subsets)
Período documentado: 2022-06-01 hasta 2023-11-30
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. In order to identify new targets to exploit DCs and macrophages for improved immunotherapy, we have: 1. Characterized the metabolic reprogramming after DC stimulation with different stimuli both in mouse and human DCs. 2. Analyzed how innate sensing connects with mitochondrial adaptations in DCs; 3. Addressed the effect of drugs targeting mitochondrial biology and the effect of genetic manipulation of mitochondrial biology on DC and macrophage function in vitro. 4. Assessed the functional in vivo effects of targeting mitochondrial biology in DCs and macrophages in homeostasis and disease.
The general project aims are: 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 final overview of the results is:
1.We found 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). In our bias approach we 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).
2.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).
3.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 and we have found essential receptors involved in this process (Cueto et al. JITC. 2021).
4.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).
5.Our novel genetic approaches based on CD11c-selective deletion of key proteins affecting OXPHOS complexes have revealed diverse results depending on the targeted complex. 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 in different organs. 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. Immunity. 2023).
In summary, we have found how genetic and pharmacologic harnessing of mitochondrial metabolism in DCs and macrophages impact their function, representing a promising tool for immunotherapy.
The final overview of the results is:
1.We found 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). In our bias approach we 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).
2.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).
3.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 and we have found essential receptors involved in this process (Cueto et al. JITC. 2021).
4.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).
5.Our novel genetic approaches based on CD11c-selective deletion of key proteins affecting OXPHOS complexes have revealed diverse results depending on the targeted complex. 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 in different organs. 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. Immunity. 2023).
In summary, we have found how genetic and pharmacologic harnessing of mitochondrial metabolism in DCs and macrophages impact their function, representing a promising tool for immunotherapy.
All results described above go beyond the state of the art as explained