Leibniz MMS Days 2019 - Abstract

Koenig, Rainer

Reprogramming macrophages employing gene-regulatory and metabolic network models

Upon exposure to microbes or endogenous stimuli, resting macrophages undergo classical (leading to inflammation and resistance) or alternative (leading to tolerance) polarization into distinct phenotypes which can cause fatal dysfunction in a large range of diseases e.g. during sepsis or induced tolerance in the tumor micro environment. We investigated gene regulatory and metabolic networks to identify the essential regulators of the metabolic switch during polarization using a constraint based modelling approach based on mixed-integer-linear programming, leading to four transcription factors as the major players regulating the distinct signatures of these polarizations. Targeting these regulators by functional assays experimentally enabled to reprogram the macrophages from the tolerant into a resistant-like state. Our results suggest the predicted regulators being essential to maintain an M2-like phenotype and may suit therapeutically for reprogramming them into the resistant state.