The previous research areas have focused on mechanisms of PRR sensing in local immunity. This section will investigate the mechanisms by which innate immune functions are influenced by the metabolic and sensory status of the organism and how they interact with the CNS. Using human-derived cells and tissues, as well as mouse and Drosophila models, we will study how signaling pathways that regulate metabolism, such as insulin/insulin like growth factor signaling (ILS) or target of rapamycin (TOR) signaling, or small metabolites such as lipids (e.g. cholesterol) control PRR sensing and signaling. While the interaction of infection-dependent inflammatory signaling pathways with metabolic pathways (e.g. insulin pathway) have been extensively investigated in the past, the pathways that connect sterile inflammation and metabolic signaling remain unclear, and thus, will be a major focus in this Cluster initiative. These studies also include a new fundamental mechanism of cross-regulation of the metabolic and innate immune response, which is FOXO-dependent and operates in non-infected animals under normal physiological conditions. A second major focus of research area C will be to investigate how the CNS responds to metabolic alterations, and how this in turn affects the immune system. Neurotransmitters, neuropeptides and lipid signaling molecules, including endocannabinoids, with dual immunomodulatory and neuromodulatory functions will be analyzed. We will investigate how GPCRs of these molecules interact with PRR sensing and signaling in the brain. The aim is to decipher the signals by which the brain and the immune system communicate at the systemic level, and how metabolic alterations influence the activity of both systems.

1. Lipid metabolism and innate immune receptor signaling.

2. Metabolic sensing and innate defense.

3. Brain immune system interactions.