Mitochondrial metabolism: Metabolic reprogramming and metabolite signalling as regulators of inflammatory disease
Macrophages are key cells of the innate immune system essential for the detection and elimination of viral and bacterial pathogens, while aberrant macrophage activation can also lead to systemic inflammation and death, as observed during sepsis. The innate immune system senses microbial infection using several families of germline-encoded pattern recognition receptors (PRRs), which detect non-self, pathogen-associated molecular patterns (PAMPs). Notable examples of PRRs are the toll-like (TLR), NOD-like (NLR) and RIG-I-like (RLR) receptor families, which initiate inflammation-associated transcription factor activation and the remodelling of cellular metabolism. Metabolic reprogramming supports the functional plasticity of macrophages by promoting pathogen clearance, inter- and intra-cellular communication, and the resolution of inflammation.
Mitochondria are central to pathogen sensing and metabolic reprogramming, serving as vital signalling hubs for the execution of macrophage effector functions. These effector functions include mitochondrial reactive oxygen species (mtROS)-mediated bacterial killing, the production of metabolic signals that regulate nuclear gene expression, and the activation of supramolecular inflammatory signalling complexes. Of note, mitochondrial respiration and nucleic acid signalling has recently been shown to facilitate the activation of the NLRP3 inflammasome and pro-inflammatory cytokine secretion. Insights into the metabolic instruction of immunity has transformed the field and led to the formation of a new branch of immunological research termed ‘immunometabolism’. Importantly, this has now opened an avenue for the development of metabolically targeted therapies to treat systemic inflammatory and autoimmune disorders, such as septic shock and multiple sclerosis (MS).
We use a combination of molecular biology, mass spectrometry, respirometry, imaging and genomic approaches to dissect macrophage biology following inflammatory activation.
For more information see: Researchgate
Biography
Dylan obtained a Bachelor of science (BSc) degree in Biochemistry (2015) from the School of Biomolecular and Biomedical Science (SBBS) in University College Dublin (UCD). He was awarded the Michael G. Harrington medal and Joy Carey project prize for obtaining first place and best thesis project in the BSc (Hons) Biochemistry class. Following his degree, he completed a PhD in Immunology (2019) from The University of Dublin, Trinity College (TCD), carrying out research on inflammatory macrophage metabolism in the lab of Prof. Luke O’Neill. From 2019-2022, he undertook a postdoctoral research associate position in the lab of Dr. Christian Frezza in MRC Cancer Unit, University of Cambridge. Here, he focused on deciphering the consequences of mitochondrial TCA cycle dysfunction in kidney epithelial cells and macrophages. In 2022, he joined the lab of Prof. Mike Murphy in the MRC Mitochondrial Biology Unit (MBU), continuing his work on immunometabolism. Dylan obtained an MRC ‘Springboard to Independence’ position beginning in March 2023, where he will direct an independent research programme focused on investigating the intersection of mitochondria, metabolism, and macrophage biology. Dylan has mentored undergraduate and PhD students throughout his career and is excited for this next stage in guiding other early career scientists looking to perform research in this emerging field.
Publications
Selected Publications
Hooftman A*#, Peace C*, Ryan DG*# et al.(2023)
Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
Nature doi:10.1038/s41586-023-05720-6
*Joint-first #Co-corresponding
Lundahl MLE, Mitermite M*, Ryan DG* et al.(2022)
Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses.
eLife doi:10.7554/eLife.74690
*Joint-second
Ryan DG*, Knatko E*, Casey A et al.(2022)
Nrf2 activation reprograms intermediary metabolism and suppresses the type I interferon response.
iScience doi:10.1016/j.isci.2022.103827
*Joint-first
Ryan DG, Yang M, Prag H et al.(2021)
Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
eLife 10:e72593 doi:10.7554/eLife.72593
Ryan DG, O’Neill LAJ. (2020)
Krebs cycle reborn in macrophage immunometabolism.
Annu Rev Immunol 38, 289-313. doi:10.1146/annurev-immunol-081619-104850
Ryan DG, Murphy M, Frezza C et al. (2018)
Coupling Krebs cycle metabolites to signalling in immunity and cancer.
Nat Metab 1, 16-33. doi:10.1038/s42255-018-0014-7
Mills E*, Ryan DG*, Prag H et al. (2018)
Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1.
Nature 556, 113-117. doi:10.1038/nature25986
*Joint-first