CRA3 Inflammatory Stress

Coordinator: Michael Bauer

Adaptive responses of tissues may evoke an endogenous response such that the cell or organ is protected against subsequent, normally injurious inflammatory stress. Prominent examples are preconditioning by short periods of local or remote ischemia to limit myocardial infarction or stroke. Similarly, primed responses of the host, e.g. in the context of "trained immunity" or "disease tolerance" reflect genetically distinct and evolutionarily conserved host defence patterns dramatically altering the course of a plethora of infections and failure to achieve tissue damage control paves the way to develop organ failure and sepsis. While resistance mechanisms like "trained immunity" aim at the reduction of the number of pathogens, "tolerance" as one of the persistence mechanisms afford protection against the deleterious effects of infectious disease by metabolic adaptation irrespective of the number of pathogens. There is increasing evidence that both, non-parenchymal cells (e.g. macrophages or microglia) as well as parenchyma (e.g. hepatocytes) contribute to alterations in stress tolerance against sterile and infection-driven inflammation. The underlying signalling events are at best incompletely understood but carry potential to favourably influence the course of inflammatory diseases that reflect an enormous socioeconomic burden.
In CRA3, we propose to study time and dose-dependent signalling events explaining the above described altered response patterns of resistance, persistence or damage in sequential stress events. Training and tolerance phenomena involve PI3K-, mTOR-, and AMPK-dependent signalling events elicited by inflammation mediators (e.g. cytokines, ROS or H2S) with concomitantly altered transcription of target genes, as well as epigenomic histone marks, such as H3K4me1 or H3K4me3 and altered DNase I accessibility. Understanding the underlying mechanisms would offer novel avenues to prevent disease progression in infectious and inflammatory conditions.