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NI FEATURE: THE EDITORIAL DEBATE II-- PROS AND CONS
Year : 2017  |  Volume : 65  |  Issue : 4  |  Page : 703-705

The enigma of neuroinflammation


All India Institute of Medical Sciences, New Delhi; Department of Neurosurgery, National Brain Research Institute, Manesar, Haryana, India

Date of Web Publication5-Jul-2017

Correspondence Address:
Prakash N Tandon
Department of Neurosurgery, National Brain Research Institute, Manesar, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/neuroindia.NI_517_17

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How to cite this article:
Tandon PN. The enigma of neuroinflammation. Neurol India 2017;65:703-5

How to cite this URL:
Tandon PN. The enigma of neuroinflammation. Neurol India [serial online] 2017 [cited 2019 Dec 10];65:703-5. Available from: http://www.neurologyindia.com/text.asp?2017/65/4/703/209518




It has now been unequivocally established that neuroinflammation (NI) accompanies most of the pathologies of the central nervous system – both acute and chronic, infective and non-infective.[1],[2],[3],[4],[5] However, its clinical implications are ill-understood. Though its existence in diverse ailments including developmental disorders like autism,[6],[7],[8] traumatic brain injury,[9],[10],[11],[12] ischaemic stroke,[13],[14] neoplasms particularly gliomas,[15],[16] and host of neurodegenerative disorders especially Alzheimer disease,[17],[18],[19] Parkinson's disease,[20],[21] multiple sclerosis,[22] and even ageing,[23],[24] and metabolic syndrome,[25],[26],[27] is well documented, the precise role that it plays in the pathogenesis of these disorders remains elusive. Although probably triggered by many different initiating events, the cascade of events that follow are not necessarily identical.

The presence of neuroinflammation is revealed not on the basis of the classical signs of inflammation elsewhere in the body e.g. dolor, tumor, calor and rubor or infiltration of leucocytes, T- and B-lymphocytes and macrophages, but on the basis of cytological and molecular evidence of an innate immune response, as manifested by activated microglia and astrocytes and associated proinflammatory cytokines and chemokines. The participation of the adaptive immune system with infiltration of circulatory leucocytes or macrophages is generally delayed and variable depending upon the nature of the pathological insult.[27],[28],[29],[30],[31],[32],[33]

Microglia, considered as the resident macrophages, are the most important cells for initiation and perpetuation of neuroinflammation following an insult – exogenous (trauma, infection) or endogenous (ischaemia, ageing, degeneration, demyelination). They can sense subtle changes in their microenvironment through a variety of surface receptors.[34],[35],[36],[37] Activated microglia release a variety of pro-inflammatory soluble factors which are potentially cytotoxic. Bloch and Hong (2005) enumerated more than 30 such factors including nitric oxide (NO), hydrogen peroxide (H2O2), hydroxide ion (OH), nitrate (NOO), tumor growth factor (TGF) β, prostaglandin (PGE) 2 and a variety of interleukins specially interleukin (IL)-1, and IL-6.[38] Interestingly, microglia being the first line of defence following acute neuronal injury, also secrete a number of growth factors like brain-derived neutrotrophic factor (BDNF), epidermal growth factor (EGF), nerve growth factor (NGF), etc.[39],[40],[41] The relative role of these factors in the pathophysiology of a given disorder is not well understood. Most studies are devoted to the neurotoxic aspect of this response. Bloch and Hong (2005) concluded, “Microglia are critical actors of self-propelling mechanisms of neurotoxicity.”[38]

Like microglia, astrocytes have been found to play a critical role in NI. Neuronal damage due to any etiology activates astrocytes which secrete a variety of cytokines.[42],[43],[44],[45] The glial response results in deleterious effects on neurons through the production of pro-oxidant reactive species as well as proinflammatory cytokines and prostaglandins.[46] In general, the astrocytic response follows the microglial response and is not as vigorous.[19]

Surprisingly, neurons themselves appear to play an active role in NI. A number of their products like cyclo-oxygenase 2, neuronal membrane proteins cluster of differentiation (CD) 22, 47, 200, fractalkine, intracellular adhesion molecule (ICAM), neural cell adhesion molecule (NCAM), semaphoring, regulate inflammation.[47],[48],[49],[50]

Thus, a central nervous system (CNS) insult results in the release of a number of cytokines and chemokines, which generate an inflammatory cascade resulting in the synthesis of various downstream mediators, the prominent among these being IL-1α and IL-1β.[18],[41],[51] While most of these cytokines come from microglia and astrocytes, in obese as well as diabetic patients and in patients with metabolic syndrome, their source could be the peripheral adipose tissue.[52],[53],[54] Similarly, pre-existing systemic inflammation exacerbates any ongoing NI.[55],[56],[57],[58],[59],[60],[61]

Notwithstanding the vast literature that has accumulated on NI during the last decade or so, a number of questions remain unanswered. It is not clear whether the inflammatory process involved in different CNS pathologies is identical, similar or disease specific. That it is similar so atleast in the case of neuroinflammation secondary to infective disorders – viral, bacterial, mycobacterial or fungal – is evident from histopathological studies. Whether or not, at the molecular level there are differences, in acute (traumatic, infective or vascular) pathologies compared to chronic degenerative conditions, has not been unequivocally resolved.

Does the inflammatory cascade involve identical elements in a similar temporal sequence in all pathologies or is it specific to a given condition? The precise manner of the cross-talk between various cellular elements involved and the cytokines and chemokines produced is not available. We still do not fully know what makes the initial acute response result in a chronic persistent inflammation, which is a hall-mark of all neurodegenerative disorders. Similarly, it is not clear how a single acute brain injury results in Alzheimer disease-like pathology, years later.[11],[12],[62],[63],[64],[65]

Based on this evidence for the role of NI in the pathogenesis of diverse neurological disorders, it was hypothesized that preventing or controlling the inflammation should result in amelioration of its role in progression of the primary disease. Thus, therapeutic trials, clinical studies and animal models were advocated for autism,[66] traumatic and ischaemic CNS insults,[67] multiple sclerosis,[68] Huntington's disease and several others disorders.

This premise was further supported by a number of epidemiological studies revealing slowing down of progression of Alzheimer's disease among individuals receiving non-steroidal anti-inflammatory drugs (NSAID) for other concomitant disorders like rheumatoid arthritis.[69] Besides NSAIDs, other anti-inflammatory drugs like corticosteroids, cyclooxygenase (COX) 1 and COX 2 inhibitors have been used.[70] For reasons not yet clear, in most instances, no unequivocal benefit has been discernible. This is even more surprising since promising results were observed in animal models of these diseases.



 
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