The stress response enzyme, Heme Oxygenase 1 (HO-1), has been identified as an important immunomodulator which is highly upregulated in response to cellular stress and inflammation. HO-1 catalyses the conversion of free heme into the linear tetrapyrroles, biliverdin and bilirubin, with the concomitant release of carbon monoxide. Interestingly, HO-1 and its reaction products have been reported to be protective in various models of autoimmune and inflammatory disease, which is largely achieved through its activity in myeloid cells such as dendritic cells (DC). Despite the promising therapeutic potential of the HO-1 system, implementation of HO-1-based therapies is hindered by the lack of clinically suitable HO-1 inducers and products. The plant-derived polyphenols, carnosol and curcumin, have been identified as candidate HO-1 inducers, however, there has been limited investigation into their effects on human immune cells.
We demonstrate that treatment of human DC with carnosol or curcumin limits DC maturation, reduces pro-inflammatory cytokine production, and prevents induction of allospecific T cell responses, via inhibition of the mitogen-activated protein kinases (MAPKs), MEK and p38. Furthermore, the anti-inflammatory effects of these polyphenols in human DC were dependent on HO-1 activity. We also report for the first time that the induction of HO-1 by carnosol and curcumin is dependent on their activation of the cellular metabolic sensor, 5’ AMP-activated Protein Kinase (AMPK), and that these polyphenols can limit the metabolic reprogramming which occurs during DC maturation. These results therefore describe the immunological effects of carnosol and curcumin in human immune cells, and, furthermore, provide important insight into the relationship between HO-1 and immunometabolism. Thus, this study supports the use of these naturally-derived compounds as alternative modulators of the HO-1 system, with relevance for the treatment of autoimmune and inflammatory diseases.