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Yoshimura et al. Neuroimmunol Neuroinflammation 2020;7:264-76 I http://dx.doi.org/10.20517/2347-8659.2020.22 Page 271
[9]
in vitro , suppression of IL-6 by Areg may play a key role in astrocyte regulation. In addition, Areg has
[97]
been postulated to be directly involved in the proliferation of neural stem cells .

Enkephalin
[98]
Prepro-enkephalin is produced in Regulatory T cells . Pharmacologically active encephalin has been
[99]
reported to be therapeutic for stroke . Opioid growth factor ([Met(5)]-enkephalin) is also neuroprotective
in the murine EAE model [100] . However, some studies indicate that preproenkephalin accelerates the
generation of autoimmune IFN-γ-producing T cells and exacerbates EAE [101] .

PPARγ
PPARγ levels are high in brain Tregs. PPARγ agonists have been reported to increase accumulation of
adipose-tissue Tregs and improve insulin sensitivity [102] In particular, PPARγ agonists have a protective
effect against various types of injury to the brain [103] . Thus, it is possible that PPARγ is involved in Treg
expansion in the brain, which should be further investigated.

TREGS AND HUMAN CNS INFLAMMATORY DISEASES
Accumulation of Tregs in the human brain of ischemic stroke patients has not been clearly shown.
However, a correlation between peripheral blood Treg/Th17 ratio or IL-17/IL-10 levels and stroke
prognosis has been reported in human stroke [104-107] . An inverse correlation between the number of Tregs in
the peripheral blood and the severity of stroke has also been reported in patients [13,108] .

It has been established that neural inflammation plays important roles not only in cerebral infarction, but
also in various types of damage to cerebrospinal tissues. These include spinal cord injury, autoimmune
diseases such as multiple sclerosis, and in neurodegenerative diseases such as Alzheimer’s and Parkinson’s
diseases. Innate and adaptive immunity may be involved in these neural inflammations. Although Tregs
have been shown to infiltrate and accumulate within the CNS [109] of neuroinflammatory diseases, role of
Tregs in such diseases have not been well characterized. Since Tregs of MS patients have been shown to
[88]
proliferate by serotonin stimulation , Tregs in the CNS diseases may be similar to the brain Tregs that
have been characterized in a murine ischemic stroke model.

CONCLUSION
In summary, brain macrophages as well as brain Tregs play important roles in the resolution of
inflammation and neural recovery. The conversion mechanism from inflammatory macrophages to tissue-
repair macrophages and the mechanism of expansion of brain Tregs by recognizing self-antigens in the
cervical LN and the brain remain to be described. Neuroprotective factors such as IGF-1 from macrophages
and Areg produced by brain Tregs not only suppress excessive activation of microglia and astrocytes, but
may also promote neural cell survival and neural stem cell recruitment [Figure 2] [110,111] . The molecular
mechanisms whereby macrophages and Tregs acquire brain-specific characteristics, including Maf-b/
scavenger receptor expression and serotonin receptor expression, respectively, remain to be clarified. Such
mechanisms could be used for increasing Tregs in the brain. Identification of brain factors and self-antigens
for brain-specific macrophages and Tregs may facilitate the development of therapies for not only cerebral
infarction but also other central nervous system diseases. Adoptive transfer of mesenchymal stem cells to
the brain has been proposed to treat stroke patients [112] . Similarly autologous Tregs transfer into the brain
is also possible for the treatment of cerebral inflammation. It is also important to define the role of brain
Tregs in other neurodegenerative disorders and neuroinflammatory diseases.