During the weekend, you watched a very intense soccer match, perhaps playoffs. Suddenly, the match comes to a halt because two players have hit each other with such force it makes you gasp. One of the players seems to have been bashed on the head so hard they had to be carried off the field for the rest of the game. There are rumors about serious injury, leaving many fans worried about the player’s return for finals. However, the player looks fine the next game, with no sign of injury and only a mild concussion. Still, you wonder, what are the consequences of such a head injury? Did their brain suffer permanent damage?
Brain injury – How serious is it?
Traumatic brain injury (TBI) is an unexpected injury, from a hit or a bump, that causes damage to the brain. TBIs are associated with neurodegeneration, or the process by which neurons progressively lose their function, and in chronic cases, cell death. Eventually, if the damage is severe enough, it can lead to dementia, a condition in which memory and thinking abilities are lost over time. Unsurprisingly, brain bumps can get complicated quickly, especially when an infection is present. It has been reported that between 20-50% of patients hospitalized with a TBI acquire an infection within a week of injury. These infections are thought to be caused by decreased host defenses and colonization of pathogenic microorganisms. Additionally, the risk of acquiring an infection increases if these patients undergo neurosurgery due to the requirement of immunosuppressive treatments, which can severely limit our ability to fight infections. How our brains heal following a TBI remains poorly understood, and many questions remain regarding how the immune system may be involved in the brain and why infections can interfere with the healing process.
Unlucky circumstances – How infections change the course of injury repair
Answers to some of these questions were investigated by Dorian McGavern’s group at the National Institute of Health, Bethesda in an article published in Nature immunology. Systemic infections, which affect the whole body, can slow wound healing, but until now it was not well understood how infections can affect repair in the central nervous system (CNS). The CNS, which includes our brain and spinal cord, is well protected by a highly controlled barrier, blood vessels and neural networks. However, this barrier can be damaged by brain injuries, which results in damage to the meninges (the three membranes that surround the CNS), leakage of the barrier, bleeding, brain swelling, cell death, and inflammation. If brain leakage is not resolved, it can result in neuronal cell death. McGavern’s team found that systemic infections affect injury repair in the CNS through a series of experiments using a mouse model of brain injury, known as mild TBI (mTBI), which induces blood vessel injury and cell death.
First, they observed biopsies of mTBI mouse brains under the microscope with the help of fluorescent markers to identify healthy and functional blood vessels following injury. Within a week, the lesions on these mice were revascularized, indicating successful injury repair. To study the influence of infections, they infected a group of mice that had received a mTBI with lymphocytic choriomeningitis virus (LCMV) Armstrong, a common pathogen used to study immune function in mice. This infection caused inflammation of the meninges, impairment of injury repair, and reduced revascularization when compared with uninfected mice. After a series of experiments testing other infectious agents, the results suggest that systemic infections can severely impact brain injury repair, independent of the type of pathogen.
Inflammation – A blessing and a curse
How can infections change the way we repair an injury? The connection between these two events is actually well-known. Repairing processes, as well as our body’s response to infection, are both closely regulated by immune cells, specifically myeloid cells. These cells quickly migrate from the periphery to the site of injury or infection, where they are activated to ingest infected or dead cells and produce inflammatory cytokines, which are the molecular messengers that coordinate immune responses. The authors wanted to first define the role of myeloid cells in CNS injury repair. They examined different populations of macrophages, which are derived from myeloid cells, in uninfected mice that had received an mTBI. They found that inflammatory macrophages (related to inflammation and killing of pathogens) accumulated gradually in the lesion after 5 days of injury, and wound-healing macrophages (or sometimes called anti-inflammatory macrophages) accumulated in the lesion perimeter. When LCMV infection was introduced into the system, however, it changed the distribution of these macrophages at the site of injury. Now, inflammatory macrophages accumulated in the lesion perimeter together with a high number of wound-healing macrophages, impacting the wound healing process in the brain and likely favoring a more inflammatory response (Figure 1).
Considering how infections can lead to inflammation, the final question in this study focused on understanding whether infection could change the inflammatory properties of the cells accumulating at the site of injury. The authors found that IFN-I (or type I interferon), a key inflammatory cytokine, is participating in this change. They detected an increased production of IFN-I in mTBI mice infected with LCMV, which may hint at the changes in the macrophage population at the site of injury. In order to study the role of IFN-I signaling on monocytes and macrophages specifically, they removed the ability of these cells to respond to IFN-I by deleting the appropriate IFN-I receptor (IFNAR), which is the molecule found on the cell surface that transmits IFN-I signaling within the cells. They found that without IFNAR, the vasculature repair was restored in LCMV-infected mice. The priority for these monocytic cells, it seems, is to remove the infection at the cost of healing brain trauma, which as we know can have serious consequences.
A bump in the head can really shake up our brain’s well-controlled environment, but thankfully we are equipped with myeloid cells that can repair the damage without major repercussions. If a systemic infection develops, however, these cells will shift their function to clear the pathogen, and the repair process is delayed. This delay can bring more serious consequences, including neurodegeneration and permanent loss of brain function. We should avoid head trauma at all costs, but at least these authors have started to shed some light into what goes on inside our injured brain, and in the future, we may be able to modulate our immune system to prevent the serious consequences of infection following a TBI.
Journal Article: Mastorakos, P., Russo, M.V., Zhou, T. et al. Antimicrobial immunity impedes CNS vascular repair following brain injury. Nat Immunol 22, 1280–1293 (2021). https://doi.org/10.1038/s41590-021-01012-1