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.
