Neuroinflammation: Damaging the Body's Information Superhighway
Neurons form the information superhighway within our bodies. The information that they process and transmit allows us to sense our world and move about it. Neurons regulate our bodies’ functions and help us respond to stimuli, including those that we’re conscious of and those that operate beneath our awareness.
But, as my fellow Michiganders can tell you, roads and highways can crumble. This, unfortunately, can happen to neurons, as well. The breakdown of the neuronal superhighway is associated with crippling neurodegenerative diseases and conditions that impact patients’ quality of life and lifespans. Information no longer flows seamlessly. Messages are lost. Our ability to react to stimuli is stunted.
The death of neurons and the loss of their function are observed in diseases of the central nervous system (like in Alzheimer’s disease and Huntington’s disease), can result from injury to the brain or spinal cord, and can arise in the progression of diseases in the retina and other sensory systems.
Death of neurons is a serious medical problem, and the neurodegenerative diseases and conditions mentioned above have no cure. Researchers have searched for years for neuroprotective therapies, but promising drugs with highly touted preclinical data failed to have benefit in patients. There are likely many reasons why past attempts have been unsuccessful. Some attempts focused on preserving the cell body of the neurons, but didn’t prevent the loss of the neuron’s axon, the branch-like projection off of the cell body. Without their axons, the neurons were functionally deficient, resembling a postal system with only post offices but no mail delivery trucks. Other attempts have failed because of the limited translatability of preclinical models to human disease. In these cases, the preclinical models failed to adequately mirror the human condition, and promising data from the models couldn’t be replicated in people. Ultimately, many attempts at neuroprotection may have stumbled because the biology of neurodegeneration, and therefore neuroprotection, is complicated.
One increasingly appreciated aspect of neurodegeneration is the contribution of the immune response. While neuroinflammation wasn’t a primary focus when I previously wrote about the connection between the nervous system and the immune system, inflammation and the immune response are strongly tied to neurodegenerative diseases and conditions.
In spinal cord injury, higher levels of inflammatory cytokines have been observed in patients. Levels of IL-1 family members are elevated, as are IL-18 and TNF. These inflammatory cytokines contribute to an inflammatory microenvironment and continued cell damage. Higher complement levels, another key family of inflammatory molecules, have also been observed in the blood following spinal cord injury, similar to the linkage between complement factors and key neurodegenerative retinal diseases. Additionally, as these cytokines help generate an inflammatory microenvironment, innate immune cells – the immune system’s first responders – are recruited to the site of injury and are thought to contribute to additional tissue damage.
Similar features are observed in the brain, both after traumatic brain injury and in neurodegenerative diseases that target neurons in the brain. Immune cells, like monocytes, neutrophils, and T cells, have been shown to traffic to the brain following traumatic brain injury. These cells complement the inflammatory activity of the microglia and macrophages that reside in the brain and lead to elevated inflammatory cytokine production. Intriguingly, activated immune cells can be found in patients for up to one year following a single brain injury, and these cells were associated with continued neuronal degeneration. These findings suggest chronic inflammation develops following acute brain injury and leads to continued, long-term neuronal damage, though additional work is needed to better understand these observations. Inflammation has also been associated with chronic neurodegenerative disease, like Alzheimer’s disease and Parkinson’s disease. In Alzheimer’s disease, for example, the accumulation of amyloid beta – widely considered a hallmark of the disease – is thought to activate an inflammatory response. Amyloid beta is able to bind to key cell signaling receptors – including the toll-like receptor family members – that are involved in the immune response. Binding to these receptors activates the production of additional inflammatory proteins, building the inflammatory microenvironment and leading to immune cell-mediated destruction of neurons.
These observations apply to the eye, as well. The retina is packed with specialized neurons, and the root cause of vision loss in many retinal diseases is the death of neurons. While glaucoma, for example, is associated with elevated intraocular pressure (IOP), vision loss is ultimately due to death of retinal ganglion cells (RGCs) and their axons, which project along the optic nerve to the brain. Preclinical models of glaucoma have demonstrated that pro-inflammatory microglia are activated, and inflammatory cytokines are produced, similar to what is seen in CNS diseases. Other chronic neurodegenerative retinal diseases, like age-related macular degeneration (AMD), have been associated with pro-inflammatory complement signaling, microglia activation, and elevated inflammatory cytokine levels in patients, likely indicative of chronic inflammation.
As you can see, inflammation and the immune response contribute to neurodegeneration throughout the body. Based on the shared feature of inflammation, it may seem obvious to try to treat all of these debilitating diseases with drugs that shut down the immune response. While this approach may work, the reality may be more complicated. It turns out that the innate immune system, for all the damage it can do, may also be involved in neuronal repair and repression of neuroinflammation. In spinal cord injury, for example, researchers have shown that innate immune cells are involved in both the damaging and repair of neuronal tissue. Other researchers tested treating patients with anti-inflammatory drugs following traumatic brain injury, but these trials failed to significantly improve patients’ outcomes. It was reasoned that broadly shutting down the immune system prevented certain immune cells from clearing out the cellular debris that was generated by injury. Similarly, such treatments may also have blocked the immune system’s role in wound healing. In other CNS injuries, it’s known that T cells (a major immune cell type) produce IL-4, a protein that can stimulate axonal regrowth after injury. Microglia, resident immune cells in neuronal tissue, also exhibit two-faced tendencies. While they can contribute to the killing of neurons in diseases like Alzheimer’s and glaucoma, they also possess key functions in maintaining proper signal transduction across neurons, acting as cleanup crews and repair workers. In fact, some researchers suspect that the microglia-induced killing of neurons seen in neurodegenerative diseases may be due to overaggressive cleanup activity by the microglia due to the inflammatory microenvironment.
Targeting the neuroinflammation associated with neurodegeneration may be a useful approach for neuroprotection, though it’s doubtful that generic anti-inflammatory drugs like steroids and non-steroidal anti-inflammatory drugs will be sufficiently protective. These may too broadly shut down the immune response, including the cleanup and repair functions. Indeed, studies with anti-inflammatory drugs in patients with traumatic brain injury showed no effect or actually worse outcomes. This likely necessitates the development of more targeted immunomodulatory approaches. Interestingly, in acute brain injury, there is some evidence that administering estrogens can prevent long-term negative outcomes associated with these types of injury, possibly overlapping with the findings of Durga Singer and her work on the immune response in metabolic disease. While it remains to be seen if targeting the immune response in neurodegenerative diseases will be sufficient for neuroprotection, this approach could be used, if it yields promising data, in combination with additional therapeutics. Perhaps with the right set of arrows in our quiver, we’ll one day be able to protect our neurons and mitigate the devastating effects of neurodegenerative diseases.
Special thanks to Qiagen and Todd Festerling for sponsoring the blog.
References and Further Reading:
Bastien D & Lacroix S. Cytokine pathways regulating glial and leukocyte function after spinal cord and peripheral nerve injury. Exp. Neurol. 2014. 258:62-77.
Popovich PG. Neuroimmunology of traumatic spinal cord injury: a brief history and overview. Exp. Neurol. 2014. 258:1-4.
Russo MV & McGavern DB. Inflammatory neuroprotection following traumatic brain injury. Science. 2016. 353:783-785.
Stocchetti N et al. Neuroprotection in acute brain injury: an up-to-date review. Critical Care. 2015. 19:186.
Newcombe EA, et al. Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease. J. Neuroinflammation. 2018. 15:276.
Krishnan A, et al. A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma. J. Neuroinflammation. 2019. 16:184.
Almasieh M & Levin LA. Neuroprotection in glaucoma: animal models and clinical trials. Annu. Rev. Vis. Sci. 2017. 3:91-120.