The degeneration of the central nervous system (CNS) is characterized by chronic progressive loss of the structure and functions of neuronal materials, resulting in functional and mental impairments (1). While the causes associated with neuronal degeneration remain poorly understood, the incidence of neurodegeneration increases with age, in mid-to-late adult life (2). This phenomenon, which mainly affects elder individuals (3,4), occurs in neurodegenerative diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) following viral infections. Viruses are able to directly injure neurons by direct killing or induction of apoptosis (5) to leading to neuro-degeneration (6,7). Similarly, in MS, the pathological features involve the permeability of the blood brain barrier (BBB), the destruction of myelin sheath, damage of the axon, the formation of glial scar and the presence of inflammatory cells, mostly lymphocytes infiltrated into the CNS (8). The loss of myelin is manifested in clinical symptoms together with neuropathic pain, paralysis, muscle spasms and optic neuritis (9).

Neurodegeneration induced by viruses, is noteworthy since it refers to the interaction between the CNS and environmental and viral factors, and suggests an important role of immune response in neurodegeneration (10). Immune activation in the CNS, always present in viral infections, immune-mediated disorders, and neurodegenerative diseases (11), involves microglia and astrocytes (12) which constitute the resident immune cells of the CNS and play an important role in the regulation of homeostasis of the brain during development, adulthood and aging (13). In the CNS, microglia constantly survey the microenvironment by producing factors that influence surrounding astrocytes and neurons (14), particularly in response to pathogen invasion or tissue damage thereby promoting an inflammatory response that further engages a self-limiting response through the immune system and initiates tissue repair (15). However, inflammation in tissue pathology that may result in the production of neurotoxic factors amplifying the disease states, indicates the persistence of inflammatory stimuli or failure in normal resolution mechanisms (16,17). Accordingly, specific inducers of inflammation associated with neurodegenerative diseases converge in mechanisms responsible in the sensing, transduction and amplification of the inflammatory processes that result in the production of neurotoxic mediators, such as cytokines and interleukins (18,19). These neurotoxic mediators are, in general, associated with several neurodegenerative diseases including AD, MS, PD and ALS, which are commonly linked to intracellular mechanisms such as the degradation of protein, the dysfunction of mitochondria, the defects of axonal transport and apoptosis (20–22). Inflammation associated with AD, MS, PD and ALS is not typically the initiating factor of neurodegenerative disease. However, the emerging evidence on the sustained inflammatory response associated with the contribution of microglia and astrocytes in disease progression, suggest contributory important roles of effectors of neuroinflammation in neuronal dysfunction and death. In this review, we assessed the role played by these inflammatory processes in neurodegenerative diseases.

The CNS is an immune-privileged organ with the innate and acquired immune response being closely controlled in relation with the periphery. Evidence suggests that a strong inflammatory response in the periphery from systemic LPS (61) or viral infections (62) results in the subsequent infiltration of leukocytes from the periphery to the CNS with consequent neuroinflammation and neurodegeneration. An offense is followed by the initial activation of microglia, which induce the release of pro-inflammatory mediators that favour the permeabilisation of the BBB. The subsequent infiltration of peripheral leukocytes occurs inside of the CNS, including T cells and macrophages, which share several functional features with microglia (61) including, the expression of toll-like receptors (TLRs), and consequently the ability to be activated by aggregated proteins or pathogen-associated molecular patterns (61,63); the expression of class II major histocompatibility complex, and the ability to present antigens to CD4+ T cells to exert an influence on the functional phenotype of T cells (64); as well as the ability to polarise their functional phenotype towards inflammatory M1 and anti-inflammatory M2 phenotypes, which can be influenced by inflammatory T cells and the lymphocyte regulatory T cells (65). Therefore, subsequent permeability of BBB leads to the possibility that peripheral macrophages can acquire a relevant role in the outcome of neuroinflammation. Accordingly, the alteration of CD4⁺ and CD8⁺ T cells has been observed in the periphery of neurodegenerative disease patients, suggesting a persisting antigenic challenge and that T cells may play a role in neurode-generative diseases. Of note, the ratio of CD8⁺ to CD4⁺ T cells or the shift to a Tc1/Th1-type immune response may contribute to a harmful brain inflammatory reaction, and the presence of antibodies against neuronal antigen observed in neurodegenerative diseases (some of them being pathogenic), solidify the involvement of the immune system in neurodegenerative diseases (5). Consequently, an acute neuro-inflammatory response is beneficial to the CNS, minimizing the injury by activating the innate immune system (66,67). By contrast, chronic inflammation is characterized by the long-standing activation of microglia that sustained release of inflammatory mediators, leading to an increase of oxidative and nitrosative stress which perpetuate the inflammatory cycle (68), further prolonging inflammation (54,69), which is detrimental for several neurodegenerative diseases (70).

However, cell factors that influence microglial fate invade the epithelial cells of the BBB while T cells infiltrate the CNS, astrocytes and neurons (71), the most abundant glial cell population of the CNS which also participates in the innate immune response, triggered as a consequence of constant insult during inflammation or infection. Astrocytes are reservoirs of HIV-1, playing significant role in virus-mediated neurodegeneration (17,57). Accordingly, chronic neuroinflammation and microglia activation play central roles in the pathophysiology of neurodegenerative disease. For example, IL-1-positive activated microglia, colocalized with amyloid β plaques and neurofibrillary tangles in AD or present in degenerative motor neuron regions in patients suffering ALS (72) lead to abnormal phosphorylation of τ (73). Similarly, neurotropic viruses trigger long-term neuroimmune activation to underlying mechanisms of viral neurodegenerative diseases (74). Furthermore, neuroinflammation has been associated with either the cause or consequence of chronic oxidative stress, a key feature of all the neurodegenerative diseases that causes genetic structural alteration, lipid and protein, resulting in neurodegeneration. Microglial cells are the main source of reactive oxygen species and nitrogen species, tumor necrosis-α and glutamate, all of which are neurotoxic when released at a high dose after the activation of microglia (71,75,76) (Fig. 2), likely due to the stimulus from TLRs through the aggregated proteins (77,78) as is the case of AD patients (79), (MS) (9), PD (80), and ALS (81).

Neuroinflammatory disorders are conditions involving the immune response damage component of the nervous system. In the CNS, inflammatory effectors derived from innate and acquired immune systems as well as glial cells, particularly, microglia, act as sensors for disturbed brain tissue homeostasis and accumulate locally in response to neuronal cell injury or foreign entry in the brain; the differential activation of microglia cells being the central point that regulates neuroinflammation, which results in neurotoxicity or neuroprotection. The environmental exposure is therefore, the critical element for the fate of neurons with regard to degeneration or protection. Additional studies must be undertaken to benefit from the versatility of microglia, since activated microglia can also produce anti-inflammatory mediators and neurotrophic factors such as insulin-like growth factor-1, glial cell-derived neurotrophic factor, brain-derived neurotrophic factors and other factors (82–84), and procure beneficial effects.