The talk will explore the role of extracellular chromatin in driving immune pathology in chronic and acute inflammatory conditions. Chromatin plays distinct proinflammatory roles during atherosclerosis but is also detrimental during sepsis and other severe conditions. However, the mechanisms regulating the release of cell free chromatin and its modes of action are unclear. We will first discuss the role of extracellular chromatin in driving neutrophil extracellular trap-driven inflammation and highlight its mechanisms of action. We will then explore the sources of cell free chromatin in sepsis and the events occurring in the spleen that lead to its release during systemic infection. Our recent data uncover a model where the capture of microbes by splenic macrophages sets off a pathogenic programme with extracellular chromatin at its epicentre, that promotes hyper-inflammation and immune dysfunction in the innate and adaptive compartment during sepsis. Finally, we will discuss the impact of chromatin clearance pathways in the regulation of pathology during acute infections.