An ischemic stroke not only causes local brain tissue damage but also triggers a pronounced systemic immune response. A central element of this reaction is the release of cell-free double-stranded DNA (cfDNA), originating predominantly from activated neutrophils. This cfDNA acts as a potent danger signal and is taken up by immune cells, where it activates the AIM2 inflammasome—a cellular sensor that induces the release of the inflammatory cytokine IL-1β. This process substantially contributes to systemic inflammation, increases susceptibility to infections, worsens pre-existing comorbidities, and can even drive early secondary strokes. Although cfDNA is known to be a major driver of this immune activation, the molecular mechanisms underlying its uptake and intracellular processing remain only partially understood.

The project funded by the Else Kröner-Fresenius-Stiftung therefore aims to systematically investigate how immune cells detect, internalize, and process cfDNA. The study focuses on the surface receptors involved—such as RAGE, Toll-like receptors, or Fc receptors—as well as on the specific forms of endocytosis that mediate cfDNA entry into the cell. In addition, it examines how endolysosomal signaling pathways, ion channels, and the acidic environment within these vesicles determine whether cfDNA is degraded or passed on as a danger signal to the AIM2 inflammasome. The project integrates advanced single-cell technologies, high-resolution microscopy, and mechanistic in vitro assays to precisely dissect each step of this signaling cascade.

In a second phase, this mechanistic insight will be tested in a disease-relevant context: a preclinical model of atherosclerotic stroke recurrence. Here, the project will evaluate whether targeted inhibition of cfDNA uptake—by blocking its receptors or combining uptake inhibition with DNase treatment—can reduce the risk of secondary ischemic events. Ultimately, this work aims to pave the way for novel immunomodulatory therapies that dampen the harmful inflammatory response after stroke without compromising the essential antimicrobial defense of the immune system.