Project A07

Immunometabolic regulation of adrenal glucocorticoid production and peripheral glucocorticoid signalling

Glucocorticoids are critical clinical tools for the treatment of many inflammatory disorders. We are interested in revealing how cellular metabolism can regulate glucocorticoid production and function. We found that acute inflammation impairs mitochondrial oxidative metabolism and increases the intra-adrenal levels of succinate, which in turn inhibits glucocorticoid synthesis in adrenocortical cells, thereby providing a mechanistic explanation of adrenal dysfunction in severe inflammation. We also showed that in the chronic inflammatory state of obesity, lipidomic remodelling and particularly changes in arachidonic acid metabolism mediate increased glucocorticoid production in the adrenal cortex. Furthermore, we investigate how immune signals impact glucocorticoid function and focus on IL-4, which is a central mediator of type 2 immunity. We identified IL-4 as a negative regulator of glucocorticoid receptor (GR) function. Moreover, polyamines, i.e. arginine metabolites which mediate IL-4 effects, also inhibit glucocorticoid signaling. These mechanisms are investigated in the adipose tissue and the bone.

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