Author: Lichy Han
The Daily Dose
Benjamin Steinberg, MD, PhD, FRCPC, a scientist at the Hospital for Sick Children in Toronto, is investigating how sepsis causes disruption of the blood-brain barrier and contributes to neurologic complications such as sepsis-associated encephalopathy.
His research focuses on inflammatory cell-death pathways and how cellular injury promotes neuroinflammation. By identifying the molecular mechanisms responsible for blood-brain barrier breakdown, his laboratory hopes to discover therapeutic targets that could preserve brain function and reduce the long-term neurologic consequences of systemic inflammation.
The neurologic consequences of sepsis
Patients with sepsis can develop encephalopathy, cognitive impairment, and other adverse neurologic outcomes. One possible cause is disruption of the blood-brain barrier, which normally protects the brain from potentially harmful substances circulating in the bloodstream.
The blood-brain barrier is formed largely by specialized endothelial cells lining cerebral blood vessels. During severe infection and inflammation, injury to these cells may increase permeability and allow inflammatory substances to enter the brain.
Understanding exactly how these endothelial cells are damaged could lead to treatments that protect the barrier during sepsis.
A different mechanism of blood-brain barrier breakdown
The prevailing theory has been that sepsis causes gasdermin D proteins to create pores in endothelial cell membranes. These pores were thought to directly compromise the integrity of the blood-brain barrier.
Dr. Steinberg’s research suggests a different mechanism. His laboratory found that the gasdermin D pores themselves may not be primarily responsible for barrier failure.
Instead, the critical event appears to be the rupture of brain endothelial cells following activation of the inflammatory cell-death pathway. This cellular rupture requires Ninjurin-1, a membrane protein involved in the final breakdown of dying cells.
These findings suggest that blood-brain barrier permeabilization during sepsis results from Ninjurin-1-dependent endothelial cell rupture rather than simply from the formation of gasdermin D pores.
Potential therapeutic importance
If Ninjurin-1 is necessary for endothelial cell rupture, inhibiting this protein or the pathway it controls might help maintain blood-brain barrier integrity during sepsis.
Such an intervention could potentially limit neuroinflammation and reduce complications such as encephalopathy and long-term cognitive impairment.
This research remains preclinical and has been conducted in cellular and animal models. Additional studies will be needed to determine whether targeting Ninjurin-1 is safe and effective in humans.
The importance of research mentorship
Dr. Steinberg credited the 2019 IARS Mentored Research Award with helping him become an independent investigator. The award provided financial support to establish research methods and generate preliminary findings that could be used to obtain additional national funding.
His earlier IARS-supported work examined danger-associated molecular patterns and their contribution to neuroinflammatory disease. That research became the foundation for his current investigations into inflammatory cell death and blood-brain barrier injury.
Dr. Steinberg emphasized that both formal and informal mentorship are extremely valuable for early-career researchers. Strong mentorship can provide scientific guidance, professional opportunities, collaboration, and support during the transition to independent investigation.
Clinical significance
Sepsis-associated neurologic injury may result partly from inflammatory destruction of the endothelial cells that maintain the blood-brain barrier.
Dr. Steinberg’s findings challenge the theory that gasdermin D pores alone cause this disruption. Instead, Ninjurin-1-dependent cellular rupture may be the critical event responsible for increased blood-brain barrier permeability.
Identifying the exact molecular pathway offers a possible direction for developing treatments that protect the brain during severe systemic infection. Although clinical application remains distant, this work provides important foundational knowledge regarding how sepsis affects the central nervous system.
Thank you to The Daily Dose and IARS for allowing us to summarize this important interview and research on sepsis-induced blood-brain barrier injury.