Neurogenic Inflammation

This article is currently under review and may not be up to date. Please come back soon to see the finished work! (23 April 2024)

Original Editor - Jo Etherton

Top Contributors - Vidya Acharya, Olajumoke Ogunleye, Simisola Ajeyalemi, Kim Jackson, Jo Etherton and Nikhil Benhur Abburi  

Introduction

Inflammation is known to be the driving factor in many diseases, including atherosclerosis, cancer, autoimmunity and chronic infections and a major contributor in age-related conditions. The classical definition of inflammation includes rubor (redness), calor (warmth), dolor (pain), and tumor (swelling), as stated by Celsus (30BC-38AD), and functio laesa (loss of function), as added by Galen (129AD-210AD). Ideally, inflammation is known to play a protective role by invading pathogens or endogenous substances such as damaged cells, and eliminates the initial cause of injury, clears the necrotic cells, and aids in tissue repair. But the complexity of the molecular, immunological and physiological processes involved in the inflammatory reaction leads to the inflammatory process in various tissues and diseases, like complex regional pain syndrome, migraine, and irritable bowel, arthritis, bladder inflammation, asthma and bladder syndromes.

Neurogenic inflammation (NI) is a physiological process in which mediators are released directly from the cutaneous nerves to initiate an inflammatory reaction in response to tissue damage or a painful stimuli. In the setting of wound healing, neurogenic inflammation helps maintain tissue integrity and facilitate tissue repair.

Mechanism of Injury

Host defense is important for the survival of any organism in order to prevent harm from tissue damage and infection. It involves 2 actions; an avoidance behavior to remove contact with a dangerous (noxious) environment (a neural function), and active neutralization of pathogens (an immune function). Traditionally, the immune system and the neurological system were thought to have distinct roles in dealing with infections and tissue injury; the immune system in charge of neutralizing infections, while the neurological system receives and transmits pain and feeling signals. However, recent research suggest that these two systems may actually work together as part of a unified defense mechanism, highlighting the interconnected nature of host defense and tissue repair.

Tissues exposed to the external environment, such as skin, lungs, urinary, and digestive tract epithelial surfaces, are extensively innervated by high-threshold pain-producing nociceptors. The transmission of harmful external stimuli is almost instantaneous, faster than innate immune system, making it the first host defense responder. Also the action potentials in nociceptor neurons travels antidromically in reverse direction towards the periphery which is known as the axon reflex. Persistent local depolarizations, result in the fast and local release of neural mediators from both peripheral axons and terminals.

It is also known that electrical stimulation of dorsal roots induces vasodilation in the epidermis, leading to the concept of neurogenic inflammation that is separate from immune-mediated inflammation. Neurogenic inflammation is initiated by activation of peripheral nervous system C-fibre neurons causing a release of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), . The mediators affect the vasculature along with directly attracting and activating the innate immune cells (mast cells/dendrites) and adaptive immune cells ( T lymphocytes)which triggers inflammation at the site that is different from the original stimuli. This integrated interaction between the immune and nervous systems serves as a protective mechanism in host defense and response to tissue injury, but can also contribute to pathology in allergic and autoimmune diseases.

Post Stroke Depression

Post Stroke Depression (PSD) is one of the most common mood disorders with depressive consequences in stroke patients. PSD affects approximately one-third of stroke patients and is a significant factor in poor recovery, negatively affecting the quality of life, functional ability and prognostic outcomes. Studies suggests that it is also linked to an increased likelihood of stroke recurrence and death. Improvement in functional abilities is associated with reduction of depressive symptoms; patients treated for depression show a better functional prognosis compared to untreated, depressed patients.

Mechanisms of inflammation

Several mechanisms correlate PSD to neurologic dysfunction. It is seen that inflammation is closely linked with depression. There is evidence of the central role of neuroinfammation in development of post stroke depression. Various studies show increase in secretion of proinflammatory cytokines interleukin (IL)‑1β, IL-6, IL-8, and tumor necrosis factor α (TNFα)..Higher serum CRP levels are linked to post-stroke cognitive impairment. Serum CRP is the most reliable stroke recovery prognostic factor.

During an ischemic injury, series of complex neurochemical events occur that are characterized by: focal cerebral hypoperfusion, bioenergetic failure, excitotoxicity, acidotoxicity, oxidative stress, microvascular injury, post-ischemic inflammation,blood brain barrier disruption and finally, death of neurons, endothelial cells, and neuroglia

Following events are seen after the onset of stroke:

• ATP levels drop as a result of imbalance between the consumption and synthesis → leads to loss of homeostasis→ allowing movement of sodium (Na) into cells→ cellular swelling (oedema)→ shriking the extracellular space.
• Also, loss of homeostasis→ results in accumulation of glutamate in extracellular space→ leads to increase influx of Calcium (Ca) into cells→ activates phospholipases and proteases→ degrades key cellular components such as membranes and proteins.
• Additionally, the elevated levels of both intracellular Ca and Na→  drive mitochondrial dysfunction & increase the production of reactive oxygen species (ROS)
• Resulting imbalance between ROS and endogenous antioxidant defences in the brain→ causes oxidative stress and marked cellular injury and/or death via degradation of proteins, nucleic acid and carbohydrates
• Additionally, ROS→ increases permeability of the BBB → allowing entry of peripheral immune cells → promoting neuroinflammation.

Acute Neuroinflammation reaction

Following cerebral ischaemia, there is activation of resident inflammatory cells, the subsequent release of inflammatory mediators, and both the migration and recruitment of leukocytes across the BBB. This robust response is initiated and sustained in the brain by various components of the ischaemic injury cascade subsequent to a stroke, such as necrotic cells, debris, and ROS.

• A specific aspect that is identified is impairment of endothelial nitric oxide synthase which plays a role in further increase in ROS by impeding nitric oxide (NO) production→ subsequently initiating activation of pro-inflammatory gene →resulting in the secretion of cytokines, chemokines, matrix metalloproteinases by inflammatory cells such as microglia and astrocytes.
• Research states that cytokines and chemokines have a role in → upregulation of adhesion molecules which in turn→ facilitates the adherence of leukocytes to the endothelium & allow their subsequent migration into the brain parenchyma.
• As a result, these processes increase cell damage and cause further disruption to the BBB, including the dysfunction of the endothelium from apoptosis of endothelial cells and detachment of pericytes.

However, the process of inflammation has a dual character.istics. Acute inflammatory response post-stroke can also be beneficial to the ischaemic environment, as it facilitates tissue repair via secretion of neurotrophic factors and removal of debris. It is also noted that astrocytes play a crucial role in facilitating neuronal regeneration by providing trophic factors and lipids, formation of the glial scar, which serves as a barrier around the infarction site and limits the propagation of inflammatory processes. Additionally, cytokines aid neuronal plasticity. In experimental trials, inflammatory cytokines including TNF-α and IL-6 have been shown to enhance post-stroke outcomes.

Inflammation resulting from stroke and depression impacts neuroplasticity, as seen by the decreased availability of brain-derived neurotrophic factor (BDNF) in synapses. A disproportionate increase in stress also causes physiological changes predisposing patients to hypertension and cardiac dysrhythmias. Individual’s emotional and social experiences triggers the activation of various components of the immune and inflammatory pathways. Cytokines act a mediator in chronic inflammatory processes linked to stroke-related complications

Factors

Various factors influence the severity and duration of PSD.

• Genetic factors: Research shows that the serotonin-transporter-linked polymorphic region 5-HTTLPR and STin2VNTR polymorphisms of the serotonin transporter gene (SERT) and hypermethylation of the 5-HTTLPR s/s genes have been associated with PSD in stroke survivors.
• Location of the lesion: Various observations are noticed concerning the site of lesion and PSD with some studies indicating lesions proximal to or in the frontal pole, or the limbic area to be frequently associated with PSD, whereas other studies not supporting these topological correlations. While several studies linked PSD with lesions of the medial prefrontal cortex, thalamus, amygdala, or pallidum by defining the disruption of frontal cortico‑limbic neuronal circuits, dorsolateral prefrontal and left cerebellar hemispheric localization. Evidence shows that that neuronal degeneration can occur in distal areas of the brain several weeks to months post-stroke. This secondary neurodegeneration (SND) results in progressive death of neurons in distal regions of the brain that were not initially affected by the reduction in cerebral blood flow due to stroke but are anatomically closer to the site of infarction as confirmed by various imaging studies. Thalamus, hippocampus, and basal ganglia are the most commonly affected by secondary neurodegeneration.
• Physical disability: In some patients, physical disability may be a causation factor. There is a link between severity of impairments/disability and PSD.
• Cognitive impairments: According to various studies, there exists a link between PSD and cognitive deficits.
• Social Support: Lack of social support is associated with PSD
• Medical and psychiatric history: Personal history of depression and/or anxiety, diabetes was considered as risk factors for PSD.

Diagnosis

According to DSM-5, poststroke mood disorders are mood disorders due to stroke with depressive features, major depressive-like episode, or mixed-mood features. Patients must have depressed mood or loss of interest or pleasure along with at least two but less than five symptoms of major depression lasting 2 weeks or longer.

Resources

add appropriate resources here

References

References will automatically be added here, see adding references tutorial.