FWF P32600 - "Metabolic Immunomodulation" of natural products

Background
Aim
People Involved

Background

Macrophages are immune cells with a high degree of plasticity and functionality. They orchestrate initiation and resolution of inflammation, clear debris by phagocytosis, modulate the adaptive immune response through antigen processing and presentation, maintain tissue homeostasis and protect against infection, briefly they “SHIP” (sample, heal, inhibit and present). In order to fulfill such diverse and context-dependent activities they require polarization to distinctive functional phenotypes. In analogy to the Th1 and Th2 T-helper cells, there are the classically activated pro-inflammatory M1 and the alternatively activated anti-inflammatory M2 type as the extremes in a continuum of possible states.

Besides the expression of distinct markers and enzymes, macrophage polarization is also associated with and driven by shifts in fuel metabolism. M1 macrophages preferentially run aerobic glycolysis (similar to the Warburg effect in cancer cells), whereas M2 macrophages augment fatty acid oxidation. Recent studies paint a more complex picture. Rather than simply defining glycolysis as pro-inflammatory and fatty acid oxidation as anti-inflammatory, the shift of mitochondria from ATP generation to ROS production and the accumulation of specific metabolites as signaling molecules have lately emerged as useful determinants of  anti- and pro- inflammatory macrophages. Deliberate shaping of metabolic features in immune cells occurred as viable strategy to modulate the immune response.

Based on the existing literature, a large number of secondary plant /microbial metabolites display pro-or anti-inflammatory bioactivity. However, an influence of the natural products on cellular energy metabolism as driving hub for the observed immunomodulation has been hardly taken into account until now.