Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.
Causes Neuroinflammation is widely regarded as chronic—as opposed to acute—inflammation of the central nervous system. Acute inflammation usually follows injury to the central nervous system immediately, and is characterized by inflammatory molecules, endothelial cell activation, platelet deposition, and tissue edema. Chronic inflammation is the sustained activation of glial cells and recruitment of other immune cells into the brain. Chronic inflammation is typically associated with neurodegenerative diseases. Common causes of chronic neuroinflammation include:
Toxic metabolites Autoimmunity Ageing Microbes Viruses Traumatic brain injury Spinal cord injury Air pollution Passive smoke Blast Injury
Viruses, bacteria, and other infectious agents activate the body's defense systems, prompting immune cells to protect the affected area from damage. Some of these foreign pathogens can trigger a strong inflammatory response that can compromise the integrity of the blood-brain barrier and thus change the flow of inflammation in nearby tissue. The location, along with the type of infection, can determine which inflammatory response is activated and whether specific cytokines or immune cells will act.
Neuroimmune response
Glial cells Microglia are recognized as the innate immune cells of the central nervous system. Microglia actively survey their environment and change their cell morphology significantly in response to neural injury. Acute inflammation in the brain is typically characterized by rapid activation of microglia. During this period, there is no peripheral immune response. Over time, however, chronic inflammation causes tissue degradation and damage to the blood–brain barrier. During this time, microglia generate reactive oxygen species and release signals to recruit peripheral immune cells for an inflammatory response. Astrocytes are glial cells that are the most abundant in the brain. They are involved in the maintenance and support of neurons and compose a significant component of the blood–brain barrier. After insult to the brain, such as traumatic brain injury, astrocytes may become activated in response to signals released by injured neurons or activated microglia. Once activated, astrocytes may release various growth factors and undergo morphological changes. For example, after injury, astrocytes form the glial scar composed of a proteoglycan matrix that hinders axonal regeneration. However, more recent studies revealed that glia scar is not detrimental, but is in fact beneficial for axonal regeneration.
Cytokines Cytokines are a class of proteins that regulate inflammation, cell signaling, and various cellular processes, such as growth and survival. Chemokines are a subset of cytokines that regulate cell migration, such as attracting immune cells to a site of infection or injury. Various cell types in the brain may produce cytokines and chemokines, such as microglia, astrocytes, endothelial cells, and other glial cells. Physiologically, chemokines and cytokines function as neuromodulators that regulate inflammation and development. In the healthy brain, cells secrete cytokines to create a local inflammatory environment that recruits microglia and clears the infection or injury. However, in neuroinflammation, cells may sustain cytokine and chemokine release, which may compromise the blood–brain barrier. Peripheral immune cells are called to the site of injury via these cytokines and may now migrate across the compromised blood brain barrier into the brain. Common cytokines produced in response to brain injury include: interleukin-6 (IL-6), which is produced during astrogliosis, and interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), which can induce neuronal cytotoxicity. Although pro-inflammatory cytokines may cause cell death and secondary tissue damage, they are necessary for tissue repair. For example, TNF-α causes neurotoxicity at early stages of neuroinflammation, but contributes to tissue growth at later stages of inflammation.
Peripheral immune response The blood–brain barrier is a structure composed of endothelial cells and astrocytes that forms a barrier between the brain and circulating blood. Physiologically, this enables the brain to be protected from potentially toxic molecules and cells in the blood. Astrocytes form tight junctions, and therefore may strictly regulate what may pass the blood–brain barrier and enter the interstitial space. After injury and sustained release of inflammatory factors such as chemokines, the blood–brain barrier may be compromised, becoming permeable to circulating blood components and peripheral immune cells. Cells involved in the innate and adaptive immune responses, such as macrophages, T cells, and B cells, may then enter into the brain. This exacerbates the inflammatory environment of the brain and contributes to chronic neuroinflammation and neurodegeneration.
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