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Page 270 Yoshimura et al. Neuroimmunol Neuroinflammation 2020;7:264-76 I http://dx.doi.org/10.20517/2347-8659.2020.22

Like other tissue Tregs, brain Tregs express Helios, which suggests that brain Tregs are derived from the
thymus embryonically. Brain Tregs possess a unique TCR repertoire and express high levels of CTLA-4,
PD-1, Areg, KLRG1, and ST2, indicating that the brain Tregs share common features of tissue Tregs.

MOLECULES DEEPLY INVOLVED IN TREG-MEDIATED NEURAL RECOVERY
Chemokine receptors
Tissue Tregs express unique chemokine receptors in each organ. Brain Tregs express specific chemokine
receptors including CCR6 and CCR8, and their ligands. CCL20 and CCL1 in particular are highly
expressed in the cerebral infarct area. Intra-ventricular injection of CCL1 and CCL20 has been reported to
[9]
increase the number of Tregs, resulting in improvement of neurological recovery .

IL-33
[81]
Of note, IL-33 promotes tissue recovery after CNS injury and up-regulates M2 type macrophage-related
[82]
genes . Since many reports suggest that IL-33 induces the expansion of Tregs in the brain [9,12,83] , it is
highly possible that brain Tregs are involved in the beneficial effects on CNS damage [12,84] . In the skeletal
muscle injury model, local mesenchymal stromal cells express the receptor for the calcitonin-gene-related
peptide (CGRP), producing IL-33 in response to CGRP, which further promotes accumulation of Tregs
[78]
[9]
and muscle tissue repair . IL-33-expressing cells in the brain consist of astrocytes and oligodendrocytes .
Higher serum IL-33 levels in acute ischemic stroke patients correlated positively with better prognosis, as
[85]
compared with those with lower IL-33 levels. These patients presented with poorer outcome suggesting
that IL-33 is protective to stroke.
Serotonin receptor
As earlier described, tissue Tregs express a common set of genes among various tissue Tregs, while each
organ-specific Treg expresses tissue-specific genes. Unlike other tissue Tregs, brain Tregs express several
unique CNS-related genes. For example, brain Tregs express serotonin receptor 7 (Htr 7), which increases
cellular cAMP . It has been acknowledged that cAMP promotes the Treg proliferation and thereby
[86]
[87]
potentiating Treg functions . Serotonin was reported to decrease Th1/Th17 cytokines, but increased Treg
[88]
population in multiple sclerosis (MS) patients . Serotonin further activates Tregs from the ischemic brain
in vitro in an Htr7-dependent manner. The administration of serotonin or a selective serotonin reuptake
inhibitor (SSRI) thus increases the number of brain Tregs in the chronic phase after stroke onset, improving
[9]
neurological symptoms . Many reports suggest that SSRI ameliorates neurological symptoms after stroke
onset [89,90] , although some studies did not prove that functional recovery improved . It is highly likely that
[91]
brain Tregs work on neuronal repair in human stroke patients.

Amphiregulin
2+
Hypertrophic astrocytes exhibit increased Ca signaling, which leads to the increased expression of pro-
inflammatory cytokines (IL-1β, IL-6) and chemokines (CCL3, CCL5) expression, promoting the formation
of glial scars . Amphiregulin (Areg) is also known to suppress the production of inflammatory cytokines,
[92]
[93]
including IL-6 and TNFα, in several inflammatory diseases .
Areg from brain Tregs has been described to suppress the excessive activation of astrocytes, so-called
astrogliosis or reactive astrocytes, which is then reported to lead to a delay in the recovery from ischemic
[94]
stroke or spinal cord injury . Although astrogliosis would be necessary for forming scars in order to
demarcate the ischemic regions from the surrounding healthy tissue, excessively activated astrocytes can
[95]
produce neurotoxic factors, resulting in neural cell damage . Areg further suppresses apoptosis of neurons
[9]
by suppressing excessive astrocyte activation . The molecular mechanism of suppression of astrocyte
activation by Areg has not been completely elucidated. Among inflammatory cytokines, IL-6 is important
[96]
for astrocyte activation . Since Areg suppresses IL-6 expression in microglia and astrocytes in vivo and