Periodic Reporting for period 4 - Metabinnate (Metabolic crosstalk in the regulation of inflammation)
Reporting period: 2023-12-01 to 2025-05-31
This project concerns how cells of the immune system use nutrients when they are being activated during infection of tissue injury. The immune system defends us from bacteria, viruses and micro-organisms, helping to clear them from our bodies and also repair any injury caused. However, sometimes it doesn't work properly or can go into overdrive, causing infectious and inflammatory diseases. The ERC project builds on exciting new insights into how the cells of the immune system take up nutrients but as well as using them for energy and as building blocks, it uses them as signals. We made three key findings. Firstly that the metabolite L-2-HG can regulate the production of inflammatory factors by macrophages, frontline cells of immunity. Secondly that another metabolite called itaconate, can dampen down inflammatory responses via mechanisms involving targeting coagulation but also by affecting mitochondria, such that they release their RNA and drive Type I interferons, which are important anti-viral cytokines. Thirdly we uncovered a whole new role for the metabolite fumarate. We found that it can decrease a cytokine called IL10, promoting inflammation, but can also drive Type I interferons. These results are therefore indicating possible new approaches to treat inflammatory diseases or to promote anti-viral immunity.
This project concerned the role of 3 metabolites in immunity: malonyl-CoA, 2-HG and itaconate. The progress on these is as follows:
1. Malonylation of GAPDH was the key target explored and we have been following up on additional targets including the enzyme ACOD1 which regulates itaconate production. We have found that IRG1 can be regulated at multiple levels, including via the transcription factor ETS-2.
2. 2-HG is the second focus since we found a major elevation in the L-isomer of 2-HG in LPS-activated macrophages. We have found that this metabolite is a key regulator of the transcription factor HIF-1alpha and can control inflammatory cytokines such as IL-1beta. Of particular interest is the role of L-2HG dehydrongenase as a controller of 2-HG. This is a wholly novel discovery in immunity since this has been neglected as a control point in macrophages. This will be explored further in the next phase of this aspect. We have found that LPS can decrease expression of L-2HG and this may be a mechanism whereby LPS elevates L-2-HG. This will be explored further.
3.Key progress has been made with the metabolite itaconate. This metabolite has become a focus for many labs, partly based on the pioneering work that was carried out in my lab. It is an anti-inflammatory metabolite that acts via modification of cysteines on target proteins. We have found that NLRP3 is a key target. A second wholly novel aspect of itaconate is the ability of a derivative, 4-OI, to block coagulation. Derivatives of itaconate are being pursued by another company I co-founded, Sitryx. We also found that the related compound, DMF, which is already in the clinic as an anti-inflammatory in multiple sclerosis, can also act as an anti-coagulant. Infectious diseases like sepsis, and also COVID19, are coagulopathies and so this work we feel has tremendous clinical potential. The target for itaconate and DMF is induction of Tissue Factor, the key driver of the coagulation cascade. These metabolites also block pyroptosis, limiting Tissue Factor release. We are exploring the interface between itaconate and coagulation further.
Finally, we have also found that itaconate can inhibit JAK1, a key inflammatory signal in macrophages and T cells. The derivative of itaconate, 4-OI, has potential as a wholly novel inhibitor of JAK1 and possibly Tyk2. In a sub-project that has just started, we have uncovered a role for itaconate in the regulation of fatty acid synthesis. This will be pursued further.
1. Malonylation of GAPDH was the key target explored and we have been following up on additional targets including the enzyme ACOD1 which regulates itaconate production. We have found that IRG1 can be regulated at multiple levels, including via the transcription factor ETS-2.
2. 2-HG is the second focus since we found a major elevation in the L-isomer of 2-HG in LPS-activated macrophages. We have found that this metabolite is a key regulator of the transcription factor HIF-1alpha and can control inflammatory cytokines such as IL-1beta. Of particular interest is the role of L-2HG dehydrongenase as a controller of 2-HG. This is a wholly novel discovery in immunity since this has been neglected as a control point in macrophages. This will be explored further in the next phase of this aspect. We have found that LPS can decrease expression of L-2HG and this may be a mechanism whereby LPS elevates L-2-HG. This will be explored further.
3.Key progress has been made with the metabolite itaconate. This metabolite has become a focus for many labs, partly based on the pioneering work that was carried out in my lab. It is an anti-inflammatory metabolite that acts via modification of cysteines on target proteins. We have found that NLRP3 is a key target. A second wholly novel aspect of itaconate is the ability of a derivative, 4-OI, to block coagulation. Derivatives of itaconate are being pursued by another company I co-founded, Sitryx. We also found that the related compound, DMF, which is already in the clinic as an anti-inflammatory in multiple sclerosis, can also act as an anti-coagulant. Infectious diseases like sepsis, and also COVID19, are coagulopathies and so this work we feel has tremendous clinical potential. The target for itaconate and DMF is induction of Tissue Factor, the key driver of the coagulation cascade. These metabolites also block pyroptosis, limiting Tissue Factor release. We are exploring the interface between itaconate and coagulation further.
Finally, we have also found that itaconate can inhibit JAK1, a key inflammatory signal in macrophages and T cells. The derivative of itaconate, 4-OI, has potential as a wholly novel inhibitor of JAK1 and possibly Tyk2. In a sub-project that has just started, we have uncovered a role for itaconate in the regulation of fatty acid synthesis. This will be pursued further.
Our work on itaconate is significantly advancing the field of immunometabolism. We are uncovering very interesting aspects and it may well give rise to new anti-inflammatory therapies or an area I'm especially excited about, new anti-coagulants. The link from metabolism to coagulation is unexpected and I am hoping that it will prove impactful and reawaken interest in coagulation,which is neglected among immunologists.We found that the metabolite itaconate, can dampen down inflammatory responses via mechanisms involving targeting coagulation but also by affecting mitochondria, such that they release their RNA and drive Type I interferons, which are important anti-viral cytokines. Thirdly we uncovered a whole new role for the metabolite fumarate. We found that it can decrease a cytokine called IL10, promoting inflammation, but can also drive Type I interferons. These results are therefore indicating possible new approaches to treat inflammatory diseases or to promote anti-viral immunity.
Clearly the success of Inflazome is hugely important - an Irish biotech based on research in my acquired in a very significant transaction. Many benefit, including investors, my university, the Irish exchequer, staff in the company (some trained in my lab) and hopefully ultimately patients suffering from major debilitating inflammatory diseases.
Clearly the success of Inflazome is hugely important - an Irish biotech based on research in my acquired in a very significant transaction. Many benefit, including investors, my university, the Irish exchequer, staff in the company (some trained in my lab) and hopefully ultimately patients suffering from major debilitating inflammatory diseases.