FIREALARM · Inflammatory signals of cell death

Inflammation is a natural mechanism to restore tissue homeostasis, and its deregulation causes human disease. The programmed cell death form pyroptosis elicits inflammation in a cell-autonomous and non-autonomous fashion by releasing cytokines and ‘danger’ signals. Intriguingly, immune pathology independent of cytokines has alluded to unexplored signaling circuits between cells regulating pyroptotic inflammatory reactions.FIREALARM addresses the fundamental question of the physiological origin of inflammation using convergent system-wide, organismal, cell biological, and molecular approaches. We will test the central hypothesis that endogenous intercellular signaling proteins drive sterile inflammation and shift homeostatic stable to non-resolving chronic states. We will determine paracrine activities of pyroptosis by systematic, iterative ablation of molecule release from dying and perception pathways of sentinel cells. In a complementary approach, we will identify inflammatory signals in vitro and in vivo by newly developed cell type-specific mass spectrometry-based secretomics technologies. Holistic views of intercellular signaling proteins, their exposure, and modification will determine the molecular language orchestrating communication networks between cells and enable the recognition of signals initiating, amplifying, and resolving inflammation. We will achieve a new level of molecular and organismal understanding of intercellular circuits governing homeostasis and conceive strategies to revert chronic conditions. Emerging inflammatory cell death markers will stratify molecular etiology and outcome of patients with sterile inflammatory diseases. Together, FIREALARM tackles the fundamental principles of sterile inflammation relevant for understanding the pathogenesis of chronic metabolic and age-related disorders.