Adaptive redox regulation in inflammatory macrophages

Macrophages are key players of the innate immune system and as such maintain homeostasis, initiate inflammatory and redox responses for pathogen defence, but also regulate resolution of inflammation. Supporting these functions are distinct metabolic programmes, which underlie macrophage functional phenotypes.

While recent advances have improved the understanding of macrophage metabolic programmes supporting specific activation states, it remains unclear how the redox system is regulated in macrophage activation states and during pathogen defence.

Here, I propose to investigate how redox adaptation is regulated during macrophage activation and its impact on functional phenotypes.

I will focus on the following three aims: Firstly, I will quantify expression of cystine transporter SLC7A11, which, by importing cystine supports glutathione and coenzyme A synthesis.

This will allow a better understanding of the role of cysteine during redox adaptation in comparison to the well-known heme oxygenase 1 (HO-1).

Secondly, I will disrupt key regulators of redox adaptation, including SLC7A11 and HO-1 to investigate their effect on macrophage functional phenotype. This will identify key nodes for redox adaptation in different macrophage activation states.

Thirdly, I will investigate the temporal profile of electrophilic stress and redox adaptation in response to macrophage activation and during bacterial infection.

Overall, this project will contribute to the detailed understanding of redox adaptation during macrophage activation, which is essential for pathogen defence and protection from oxidative stress.

Furthermore, identification of new drug targets for redox regulation in macrophages would provide the basis for novel therapies for oxidative stress induced pathologies.