Damage to blood vessels in the brain can happen in the form of traumatic brain injury (TBI), for example as a result of a concussion, or as cerebrovascular injury (CVI), such as during a stroke.
Whatever the cause, neurons are notorious energy hogs and rapidly die off without a steady blood supply. Leaky blood vessels also mean a damaged blood-brain-barrier (BBB), which allows many compounds to get into the brain that are best kept out. For both reasons, blood vessel repair is high on the agenda for the body after TBI and CVI.
Researchers at the National Institutes of Neurological Disorders and Stroke have demonstrated that systemic infections after either TBI or CVI impair the repair of blood vessels by competing for the services of immune cells, in particular, proangiogenic myeloid cells. Particularly in the case of CVI, that diversion led to permanent cognitive impairments and BBB defects.
Senior author Dorian McGavern, a senior investigator at the NINDS, and his coauthors wrote that their findings, which were published in the September 23, 2021, issue of Nature Immunology, "reveal a common immunological mechanism by which systemic infections deviate reparative programming after central nervous system injury and offer a new therapeutic target to improve recovery."
In their experiments, the team first showed that while mice with mild traumatic brain injury could repair their brain vasculature almost completely within a week under normal circumstances, an infection with lymphocytic choriomeningitis virus (LCMV) 4 days after the injury reduced this repair, with only roughly a quarter of vasculature being repaired after a week.
However, mice that were chronically infected with LCMV from birth and had developed immune tolerance to the virus were as quick to repair their vessels as uninfected animals, suggesting that the issue was not the infection itself, but the immune response it set off, that was the problem. A fungal infection with Candida albicans or the immune stimulating bacterial toxin lipopolysaccharide (LPS) also reduced vesicle repair.
The team next checked whether repair was delayed or permanently reduced in infected animals, and showed that mice with a single infection were ultimately able to catch up with their uninfected peers. After a month, more than 90% of damaged vasculature had been repaired.
A second infection, however, particularly in animals with CVI, permanently derailed repair processes. Such animals had leaky blood vessels both in the meninges, which are protective layers surrounding the brain, and in brain tissue itself. In previous experiments, the team had also shown that repeated TBIs had a synergistic effect on brain repair, offering one explanation for the devastating effect of repeat concussions.
The team also looked at the signaling molecules underlying the effect, and demonstrated that type I interferons (IFN-1) were important for redirecting myeloid cells away from vasculature repair and into infection-fighting roles. Genetically knocking out the IFN-1 receptor specifically in myelomonocytic cells, which play an important role in repair, restored vasculature repair to normal levels in the meninges, but was only partially effective in the brain itself, possibly because IFN-1 has negative effects on other brain-resident immune cell types as well.
The studies offer one explanation for why recovery from a stroke can differ widely in different patients. Both CVI and TBI patients are at high risk of infection, possibly due to systemic immune suppression after brain injury. Almost a third of hospitalized stroke patients contract an infection in the hospital, and 20-50% of TBI patients contract an infection during their healing phase. TBI patients remain at risk of sepsis and pneumonia years after their injury.
CVI and TBI are also tied to an increased risk of neurodegenerative disorders later in life. "Based on our data in CVI mice, we postulate that acute infections following CVI in humans can induce a chronic state of disrepair, BBB leakage and inflammation, leading to neurodegeneration," the authors wrote.