How the interaction with gut microbiota shapes the impact of neutrophils on ischemic brain injury

• Applicant: Vikramjeet Singh, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 444117227

Stroke is the leading cause of severe disability and death across the world. At present, there are a minimal number of therapeutic interventions to treat human stroke. The excessive immune cell activation after stroke act as a major contributor to enhance inflammatory brain lesions and deteriorate the recovery mechanisms. The peripheral signals involved in immune cell activation after stroke are not entirely known, and their understanding is necessary to develop new therapies for the treatment of human patients.In the last few years, several research reports have highlighted the contribution of gut microbiota in priming immunity after stroke. Recently, we have demonstrated that ischemic stroke induces massive gut microbiota alterations and initiates a T cell-dependent immune response that is detrimental to the injured brain. However, the complete understanding of the gut microbiota-immune-brain axis is still an open research question.Neutrophils constitute 50–60% of circulating cells in humans and are the first invaders of the injured brain after a stroke. Recent research findings of our group have demonstrated that neutrophils induce toxic effects on the ischemic brain, and inhibition of neutrophils invasion to the brain reduces inflammatory tissue injury. Neutrophils can sense diverse microbial signals and their activation can impact post-stroke brain injury. Moreover, activated neutrophils can influence T cell priming and their effector functions.In our new research, we attempt to investigate the impact of neutrophil-gut microbiota interactions in the two most commonly used mouse models of stroke. Our preliminary data showed a reduction in the neutrophil number in Peyer’s patches with a subsequent increase in colonic neutrophils after a stroke. Our findings showed post-stroke shifts in neutrophil dynamics in gut immune organs that might influence stroke-induced dysbiosis and inflammatory brain lesions.The specific aims of the present research proposal are 1) Determine the impact of neutrophil-gut microbiota interactions on ischemic brain injury 2) Analyze the effect of activated neutrophils on gut microbiota alterations and inflammatory brain tissue injury 3) Investigate the impact of microbiota modulation on neutrophil-induced post-stroke parenchymal and microvascular injury.

• DFG Programme: Research Grants