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The Role of Inflammation in Neurodegeneration

By: Scott Hauser, Technology Transfer Specialist, Sigma® Life Science, Biofiles, Vol. 8, No. 19

It is well established that the brain can sense and react to peripheral insults through the rapid induction of fever and other neuroendocrine changes in response to events such as infection and tissue injury. The brain and central nervous system (CNS) were once considered sites of immune privilege, largely exempt from systemic inflammatory and immune processes, based upon observations antigens and lymphocytic cells display limited ability to cross the blood-brain barrier (BBB) and elicit cell-mediated or humoral immune responses to injury or infection. In recent years, an increasing body of evidence has established that the brain and CNS are capable of initiating immune-mediated inflammatory processes that may contribute to the progression of many neurodegenerative diseases, and possibly other mental and cognitive impairments.

In healthy brain and CNS tissues, proinflammatory cytokines are undetectable or present at very low levels. Resident microglia and astrocytes regulate innate, neuroprotective immune responses that maintain brain homeostasis, but they can also initiate adaptive responses that may ultimately lead to neuronal damage. For instance, neuroprotection is maintained by the clearing of debris and necrotic cells resulting from viral infections or stress by microglia cells, and the suppression of  proliferation and effector functions of infiltrating T cells by astrocytes.  However, activated microglia and astrocytes produce proinflammatory cytokines such as tumor necrosis factor (TNF-a) and interleukin-1 beta (IL-1b), in addition to chemokines and inflammatory mediators such as prostaglandins and nitric oxide (NO).  The production of these molecules can induce the expression of adhesion molecules along the BBB, resulting in the infiltration of inflammatory cells and cytotoxic T cells that mediate neuronal damage.

A strong association between the production of cytokines, especially IL-1β, and neurodegeneration has been established in animal models. Following CNS damage, IL-1β produced by microglia leads to changes in GABA and NMDA signaling, and increased levels of NO and prostaglandins. In rodent stroke/ischemia models, administration of recombinant interleukin-1 receptor antagonist protein (IL-1ra) or IL-1β neutralizing antibodies can significantly reduce ischemic damage. Additionally, IL-1β knockout mice exhibit decreased infarct volume compared to wild type animals. In epilepsy models, administration of recombinant IL-1β enhances the intensity of induced seizures in rats, while genetically engineered mice overexpressing IL-1ra display a reduction in both the onset and extent of chemically induced seizures. Additionally, overexpression of IL-1ra or injection of recombinant IL-1ra following traumatic brain injury (TBI) reduces the degree of tissue damage and improves recovery in mice. 

Studies conducted in the last decade have led to a better understanding the mechanisms that initiate production of cytokines and other proinflammatory mediators within the CNS. Toll-like receptors (TLR) expressed in microglia, astrocytes, oligodendrocytes, neurons, and along the BBB are largely responsible for the initiation of innate immune responses in the CNS, through their ability to activate NF-κB mediated production of cytokines, prostaglandins, and NO. While short-term TLR signaling mediates neuroprotective repair mechanisms, chronic TLR activation, along with increased levels of TRL expression, have been observed in animal models of Alzheimer’s and Parkinson’s diseases. TLR-mediated activation of microglia has been reported in response to both fibrillar amyloid β, a hallmark of Alzhiemer’s disease (AD), and a-synuclein, a component of Lewy body inclusions found in Parkinson’s disease. Likewise, the purinergic receptor P2X7, which is essential for release of IL-1β, is widely expressed within the CNS, predominantly on microglia. As with TLR, animal studies have revealed a correlation between P2X7 activation with ischemia-reperfusion injury, neurodegenerative disorders such as AD, multiple sclerosis, and epilepsy. A role for P2X7 in neuropathic pain has also been reported via neuronal, P2X7-mediated glutamate release. Although there is strong evidence suggesting roles for both TLR and P2X7 in neurodegenerative disorders, their exact role in disease progression is not yet fully understood.

Finally, studies investigating the contribution of inflammatory cascades to the delayed brain damage that may occur following TBI, including chronic traumatic encephalopathy (CTE) are likely to increase, due to the enhanced awareness of the association between participation in football and other high-contact sports with an increased frequency of TBI and CTE. 

The recognition that resident cells within the CNS can initiate proinflammatory immune responses, and the increasing evidence supporting the role of inflammatory cytokines, and other important mediators including prostaglandins, NO, and complement components in the progression of neuronal damage, neurodegenerative, and cognitive disorders could potentially lead to new therapeutic approaches targeting inflammation pathways for the treatment these diseases.

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 Reference

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