Mark Haussmann

Glucocorticoids (GC), like dexamethasone and prednisolone, are widely used in medicine, but how do they actually work? This is really impressive work (Auger et al.), which figured it all out There are two mechanisms: a slow, broad response, which depends on transcriptional changes by the glucocorticoid receptor (GR) And a second, fast (but sustained) response, where GCs increase flux through macrophage TCA cycles to produce the metabolite, itaconate: Itaconate was produced systemically in response to GCs, and quickly reduced inflammation through a range of mechanisms Here's the most interesting bit: GCs only suppressed inflammation if the TCA cycle and itaconate were in tact, but this was mostly independent of GR's broad transcriptional response - suggesting that the TCA/itaconate pathway is predominant A possible consequence of this: some of the side-effects of glucocorticoids in patients, like increased fat mass and type 2 diabetes, may result from GR's broad transcriptional changes... ... so if we had more precise drugs, which exploit the itaconate response but spare the GR response, this could decouple the beneficial (anti-inflammatory) effects of steroids from the negatives Here it is: nature.com/articles/s41586-0…