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The inability to restore the previous healthy state The whole process appears, however, to be mediated
may ensue in chronic inflammation, characterized through stress, [16] which is a very general term, but it
by shifts from the main participating cells toward is essential to understand neuroinflammation as part
mononuclear (monocytes, macrophages, lymphocytes, of a whole in the pathophysiology of various disorders,
and plasma) cells and fibroblasts and from the and disease in general.
main participating molecules toward interferon‑γ,
interleukins (ILs), growth factors, nitric oxide, and There has been evidence that neuroinflammation
hydrolytic enzymes. [10] is reflected in changes in peripheral immunity, [17]
but the reverse may not be true, hence, evidence
The stress concept was developed from the work of of peripheral immunological alterations cannot be
Selye, [11,12] who viewed the body in Cannon’s frame. [13] taken to indicate the presence of neuroinflammation.
Stress, like inflammation, was proposed to be the There is no consensus as to whether central and
body’s response to “diverse nocuous agents,” [11] a peripheral immunity are specular, and a recent study
general adaptation syndrome characterized by an that adequately addressed the issue showed that brain
integrated neuroendocrine and immune response immune markers were found to be independent from
tending to restore homeostasis. Selye [12] showed the peripheral activity of the immune system. [18]
that the response also involves the immune
system, which constitutes another parallel with the Summarizing, stress may lead to the establishment
inflammatory response. Currently, the stress response of a chronic inflammatory reaction, which may
is considered to be evolutionary and likely to amplify occur in the brain in parallel to the periphery, thus
an organism’s resistance to environmental stressors. setting brain function in a sickness mode that may
Like inflammation, the inability of an organism to substitute default activity and perpetuate the disorder.
adequately address stress may lead to a stress disorder, This does not explain the oscillatory mood activity.
which in psychiatry is represented by posttraumatic The presence of neuroinflammation in the brain in
stress disorder, anxiety disorders, and mood disorders patients with bipolar disorder can help to answer
such as depression. whether neuroinflammation is a general way by
which manic‑depressive symptoms are produced.
In recent years, there has been an increasing It is not a sufficient evidence to demonstrate some
recognition of altered immunological parameters in of these symptoms in people with autoimmune
many psychiatric disorders, including depression, neuroinflammation or other disorders showing both
bipolar disorder, autism spectrum disorders, and neuroinflammation and cognitive or mood alterations
schizophrenia. [14,15] The rationale is that chronic proper of bipolar disorder. Instead, convincing evidence
inflammation, by releasing cytokines, may set requires the demonstration of neuroinflammation
brain function into a “sickness mode,” thus causing in a population of patients with bipolar disorders
psychiatric disorders. However, how this is carried out who have no other comorbidity. For this reason,
is not explained, so it remains an interesting paradigm we consider studies that point to the existence of
with no demonstration so far. neuroinflammation in bipolar disorder only those
studies investigating microglial activation or showing
WHAT DO WE INTEND BY increased presence of neuroinflammatory markers
“NEUROINFLAMMATION?” in the human brain, in people with bipolar disorder
compared to healthy or nonpsychiatric controls.
Neuroinflammation is defined as inflammation of These may be postmortem studies or studies in living
the central nervous system. It consists of increased humans that involve the cerebrospinal fluid (CSF) or
glial activation, pro‑inflammatory cytokine content, brain imaging.
blood‑brain‑barrier permeability, and leukocyte
extravasation. The process is believed to be driven Having this in mind, we aimed to review the evidence
by IL‑1 beta (IL‑1β), a cytokine that has been found for neuroinflammation in the pathogenesis of bipolar
to be increased in neurodegenerative disorders such disorder.
as Alzheimer’s disease, Parkinson’s disease, and
multiple sclerosis. IL‑1β stimulates the IL‑1 receptor/ OUR SEARCH STRATEGY TO INVESTIGATE
IL‑1 accessory protein complex to increase glia NEUROINFLAMMATION IN BIPOLAR DISORDER
nuclear factor kappa B‑dependent transcription of
pro‑inflammatory cytokines, such as tumor necrosis We performed a careful PubMed search using the
factor (TNF)‑α, IL‑6, and interferons, as well as the following strategy: (neuroinflammation* or glia* or
neutrophil‑recruiting chemokines CXCL1 and CXCL2. microglia* or [(CXCL1 or CXCL2 or IL‑1b* or IL‑6 or

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