Representatives of the Association of British Neurologists advisory group for MS and neuroinflammation discuss the role of neuroinflammation in both neurodegenerative diseases like multiple sclerosis (MS) and the ageing process
What is neuroinflammation, and is it always harmful?
Inflammation is part of the body’s normal response to injury; immune cells mobilise to the site of injury, and the production of substances known as cytokines triggers recruitment of more cells, initiating the process of repair. People who have impaired inflammatory responses experience a range of diseases, which may include vulnerability to infection. However, inflammation that is out of proportion to the injury or which occurs without a trigger, such as infection or mechanical injury, can be harmful. Indeed, disease is recognised to occur when excessive inflammation is targeted at a specific tissue or organ, e.g. joints in rheumatoid arthritis or the lungs in asthma.
In neuroinflammation, there is an inflammatory response directed at the brain and spinal cord (central nervous system; CNS) and/or nerves supplying organs and limbs (autonomic and peripheral nervous systems). The blood-brain barrier (BBB) is a selective barrier that normally protects the CNS from circulating immune cells and harmful substances. During neuroinflammation, the BBB can become more permeable, allowing immune cells and molecules that normally would not enter the brain to cross, which may amplify inflammation.
Like systemic inflammation, neuroinflammation may occur as part of a reparative or regenerative response to injury. However, when excessive or misdirected, it contributes to disease. The archetypal neuroinflammatory disease is multiple sclerosis (MS), which affects over 2.5 million people worldwide. In this condition, inflammatory cells attack and damage myelin, the cholesterol-rich substance which is wrapped around nerves in the CNS and acts as an ‘insulator’, improving the speed and accuracy of signalling in the brain and spinal cord.
When myelin is damaged, there is disruption to CNS function, resulting in neurological disability, e.g., impairment of vision, dexterity, mobility, and cognition. Although there is no cure for MS, considerable progress has been made in the development of disease-modifying medications which target specific parts of the immune system to reduce neuroinflammation, e.g. stopping the movement of immune cells known as leucocytes out of the lymphoid tissues where they are made and crossing, via the blood, into the CNS.
Whilst disease-modifying therapies targeting immune responses are well-established in MS, research is ongoing into additional interventions that may modulate neuroinflammation, such as restoring BBB integrity and lifestyle factors such as diet and exercise.
What is the role of neuroinflammation in ageing?
It is increasingly recognised that, with ageing, the balance between the beneficial and harmful effects of inflammation shifts towards tissue damage, a phenomenon often referred to as ‘neuroinflammaging.’ In addition to an overall increase in inflammation, the mechanisms responsible for focusing and limiting inflammatory responses become less effective. Consequently, prolonged harmful inflammation can persist, contributing to progressive tissue injury. This may be due to prolonged exposure to stressors such as infections or toxins (including cigarette smoke), altered sleep patterns, and changes in the constellation of organisms that colonise the gut (microbiome). It is thought that triggers such as these contribute to elevated levels of pro-inflammatory cytokines and leakiness of the BBB, which normally regulates the passage of cells from the blood to the CNS. Additionally, disturbances of glia, traditionally considered the ‘support’ cells of the brain, and mitochondria, the cells’ power sources, are thought to change the CNS environment in favour of damaging inflammation.
Senescent cells or aged cells that stop dividing but do not die, release inflammatory molecules, which are collectively referred to as the senescence-associated secretory phenotype (SASP), can fuel chronic neuroinflammation and tissue damage. Putative strategies to increase longevity via anti-inflammatory interventions are currently under investigation. These include senolytic drugs, which target dying cells and interfere with the pathways controlling cellular growth and metabolism, e.g. the function of mTOR or sirtuins.
Does neuroinflammation play a role in neurodegenerative diseases other than MS? [H3]
Given the known link between ageing and many neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), there has been increasing interest in whether neuroinflammation contributes to neurodegenerative diseases other than MS. In these diseases, ongoing inflammation can cause nerve cells to die over time, which leads to worsening symptoms. Whilst anti-inflammatory therapies are not yet available for these conditions, it is an area of active research interest. Strategies include targeting cytokines that drive inflammation and repurposing of drugs known to have anti-inflammatory mechanisms of action in other conditions, e.g., GLP-1 agonists currently used in diabetes. Furthermore, neuroinflammation has also been identified as having a role in psychiatric conditions such as depression, schizophrenia and anxiety.
What can people do to reduce harmful neuroinflammatory responses?
Whilst novel pharmacological interventions to reduce neuroinflammation in the context of the promotion of healthy ageing and treatment of neurodegenerative diseases may be available in future, many lifestyle factors currently recognised as ‘healthy’ reduce inflammation. These include not smoking, having an optimal body weight with a diet high in fruit, vegetables and mono- and polyunsaturated fats, as well as getting adequate sleep and having regular exercise. Additionally, properly managing chronic conditions such as diabetes, high blood pressure, and high cholesterol plays a vital role in lowering overall inflammation and protecting brain health.
In summary, gaining a better understanding of the mechanisms behind neuroinflammation in ageing and disease is a crucial focus of current research. This knowledge will undoubtedly help develop new treatments to support healthy ageing and combat neurodegenerative conditions. Meanwhile, certain lifestyle choices are already known to help maintain a healthy balance of neuroinflammation. Early intervention and a combination of healthy lifestyle habits alongside emerging therapies hold promise for reducing harmful neuroinflammation and improving quality of life as we age.
