Immune regulation of central nervous system functions: from sickness responses to pathological pain

Abstract

Classically, the central nervous system (CNS) and the immune system are thought to operate independently of each other. This simplistic view has been corrected in recent years, first with the recognition that the brain dynamically modulates the immune system, and later with the reverse; that is, that the immune system modulates the CNS as well. The evidence that the immune system regulates CNS functions is first reviewed. This immune-to-brain communication pathway triggers the production of a constellation of CNS-mediated phenomena, collectively referred to as 'sickness responses'. These sickness responses are created by immune-to-brain signals activating CNS glia to release glial proinflammatory cytokines. The most recently recognized member of this constellation of changes is enhanced pain responsivity. The hypothesis is then developed that pathological, chronic pain may result from 'tapping into' this ancient survival-oriented circuitry, including the activation of immune and glial cells and the release of immune/glial proinflammatory cytokines. This can occur at the level of peripheral nerves, dorsal root ganglia, spinal cord, and likely at higher brain areas. The implications of this model for human chronic pain syndromes and clinical resolution of these chronic pain states are then discussed.

Novel Phospholipid Signature of Depressive Symptoms in Patients With Coronary Artery Disease

“…For example, PA treatment in adipocytes induced expression of interleukin‐6 and accumulation of reactive oxygen species 33. These inflammatory signals can be transmitted across the blood‐brain barrier by activation of glia cells and cumulate in the release of inflammatory cytokines 34. The resulting neuroinflammation increases oxidative stress, which changes neuronal membrane stability and affects catecholamine neurotransmission, a mechanism involved in traditional depressive pathophysiology 35.…”

Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans

“…Besides signs of neuroinflammation as reflected by CSF cytokine indices, brain positron emission tomography (PET) scans of patients with chronic back pain show microglial cell specific activation (greater than healthy controls) in: 1) medial thalamic, 2) post central gyrus, and 3) paracentral lobule, suggesting that chronic pain mediated neuroinflammation and central sensitization likely co-occur in both the brain and spinal cord (Loggia et al, 2015). The mechanisms of central sensitization are known to involve neuronal interaction with activated glia cells and astrocytes (Milligan and Watkins, 2009;Watkins and Maier, 2005). Activated microglia and astrocytes release pro-inflammatory cytokines/chemokines such as TNF␣, IL-1␤, IL-6 and IL-8, in addition to glutamate and substance P, which collectively are known to amplify pain (Milligan and Watkins, 2009;Watkins and Maier, 2005).…”

“…The mechanisms of central sensitization are known to involve neuronal interaction with activated glia cells and astrocytes (Milligan and Watkins, 2009;Watkins and Maier, 2005). Activated microglia and astrocytes release pro-inflammatory cytokines/chemokines such as TNF␣, IL-1␤, IL-6 and IL-8, in addition to glutamate and substance P, which collectively are known to amplify pain (Milligan and Watkins, 2009;Watkins and Maier, 2005).…”

Minocycline modulates neuropathic pain behaviour and cortical M1–M2 microglial gene expression in a rat model of depression

“…Substantial evidence indicates dysregulation of the (neuro)immune system in both depression and chronic pain (for review see Miller et al, 2009, Watkins andMaier, 2005); which may also underlie the association between these conditions. Pre-clinical studies have demonstrated peripheral nerve injury-induced neuroimmune activation in brain regions responsible for the modulation of nociception and/or affect, including the prefrontal cortex (Apkarian et al, 2006, Al-Amin et al, 2011.…”