Inflammation in Schizophrenia: Pathogenetic Aspects and Therapeutic Considerations

Norbert Müller

Disclosures

Schizophr Bull. 2018;44(5):973-982. 

In This Article

Inflammation in the CNS

Pro-inflammatory cytokines, microglia, astrocytes, and immune cells of the peripheral immune system, including monocytes, macrophages, and T- and B-lymphocytes, are all involved in mediating inflammation in the CNS. As mentioned above, the inflammatory response is an essential process if well regulated but can harm rather than help host cells if excessive. Dysregulation of the inflammatory response can have various causes, including infectious agents, such as bacteria and viruses, and environmental toxins. It may also be a secondary reaction to trauma-related neuronal lesions or be a genetic effect.

The Role of Microglia

Microglia are the most important component of the local CNS immune system and constitute between 10% and 20% of all cells in the CNS.[20] They play the main role in neuroinflammation and provide the first line of defense in case of injury or disease. They are activated if the body is exposed to a systemic infection, eg, and are involved in the synthesis of the central, pro-inflammatory cytokines that are released in case of such an infection and result in a variety of mental states, including "sickness behavior."[21] Reports of higher levels of pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines in schizophrenia are discussed below. Positron emission tomography (PET) studies showing microglia activation are also mentioned, although the results of these studies are somewhat inconsistent.

As a caveat, it has to be mentioned that the dualism of pro- and anti-inflammatory cytokines is a simplification because certain cytokines can have both pro- and anti-inflammatory properties, depending on several factors, including dose.[22] Further discussion of this topic, however, is beyond the scope of this overview.

Besides the acute activation of microglia, a variety of low-level stimuli can cause them to be "sensitized" or "primed,"[23] a process that elicits an exaggerated immune response. Examples of such stimuli are the ageing process,[24] neurodegeneration,[25] and stress.[26] Once microglia are primed, an additional low-level stimulus, eg, minor systemic inflammation, may cause them to proliferate and increase production of pro-inflammatory cytokines,[27] which in turn may exacerbate or re-exacerbate an immune response in the CNS and be visible as an acute change in behavior.[28]

Stress-induced Inflammation in Psychiatric Disorders: The Role of Kindling/Sensitization

"Kindling," also referred to as "sensitization," is a process by which an initial immune response to a stimulus, eg, stress or infection, strengthens or lowers the threshold for a response to future exposure to the same stimulus, ie, a weaker stimulus is required to activate the immune response or cytokine release is greater than at the initial exposure. A memory function of the acquired immune system is hypothesized to be responsible for this process.[26,29] For example, in rats, release of IL-6 in response to stress was found to reactivate (prenatally) conditioned processes.[30] Exposure of healthy people to an additional stimulus, such as systemic inflammation or stress, results in activation of the immune response, including cell proliferation and increased production and release of pro-inflammatory cytokines.[27] Kindling may also provide support to the hypothesis that infection in early childhood can result in increased release of cytokines upon activation of the immune system by reinfection or another stimulus later in life, resulting in neurotransmitter disturbances.

Kindling plays a key role in immune activation. Psychopathological symptoms and inflammation are associated with the immune response to stress, and inflammation is also involved in stress-related changes in behavior induced by cytokines and mediated by neurotransmitters. Stress evokes a pro-inflammatory immune response, which normally is downregulated after the stressful event. It has been shown in experiments that after chronic stress or repeated stressful events, the threshold for the physiological reactions to stress is downregulated and a smaller stimulus suffices to trigger an immune or a neurotransmitter response. For example, one animal study showed that the aged brain is in a proinflammatory, sensitized state and shows a greater cytokine response to inflammatory stimuli than the brains of younger animals.[26] In other animal studies, re-exposure to a cytokine resulted in greater neurotransmitter responses,[31] as shown for example with TNF-α.[32] In the CNS, stress may cause activation and proliferation of microglia, which in turn may mediate these cytokine effects.[33] Kindling is at least partly due to the memory function of the acquired immune system.[26,29] Stress-associated release of pro-inflammatory cytokines is hypothesized to reactivate conditioned processes,[30] acting as a "second hit."

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