DISCUSSION
In this study, we identified the elevations of serum PRX5 and PRX6
levels in patients with MS and NMOSD and their associations with
blood–brain barrier dysfunction and disease duration in NMOSD patients.
Pathological analyses of the spinal cords from EAE mice showed
remarkable PRX5 staining in CD45+ infiltrating cells. These results
indicate that PRXs may play some role in CNS inflammation during MS and
NMOSD.
PRXs have recently received attention as novel DAMPs. Among the PRX
subtypes (PRX1-6), PRX1, PRX2, PRX5, and PRX6 are expressed in the brain
and can trigger the release of several cytokines. Furthermore, PRX5 has
the strongest effect on the activation of Th17 activation via the
secretion of IL-23 [12]. Th17 cells play
a dominant role in the development of EAE
[17] and are also thought to be involved
in the pathogenesis of MS and NMOSD [5].
Therefore, we must consider that PRXs may play a role in triggering
autoimmunity during MS and NMOSD.
Thus far, some papers about the role of PRXs in patients with MS have
been published but not in patients with NMOSD. Holley et al. reported
that PRX5+ hypertrophic reactive astrocytes were observed in the acute
and chronic brain lesions of MS patients. They also speculated that
ongoing oxidative stress occurred during the acute and chronic phases of
MS, and PRX5 was upregulated in astrocytes to neutralize oxidative
stress [18]. Voigt et al. reported that
PRX2 was upregulated mainly in astrocytes of white matter lesions.
Furthermore, its expression level was positively correlated with the
degree of inflammation and oxidative stress in patients with MS, which
suggests that PRX2 contributes to the resistance of astrocytes against
oxidative damage [19]. Yun et al.
reported that PRX6 was strongly expressed by cells with astrocyte-like
morphology in the MS lesions of human patients
[13]. The increased PRX6 expression in
astrocytes of MS patients reduced MMP9 expression, fibrinogen leakage,
chemokines, and free radical stress, leading to decreased blood–brain
barrier disruption [13]. These findings
suggest that PRX6 expression may represent a therapeutic way to restrict
inflammation in the CNS and potentiate oligodendrocyte survival.
Therefore, PRX6 may have potential as a new neuroprotective therapy for
MS [13]. Taken together, upregulated PRXs
may help protect astrocytes and maintain blood–brain barrier function.
However, no paper has described the protein levels of PRXs in patients
with MS and NMOSD thus far. In our study, serum PRX5 and PRX6 levels
were significantly elevated in MS and NMOSD patients and partly
associated with Qalb (as a marker of blood–brain barrier function), CSF
protein, and disease duration in NMOSD patients. In general, longer
disease duration correlates with more severe blood–brain barrier
dysfunction in MS and NMOSD patients. Additionally, serum PRX6 levels
were significantly associated with PRX5 levels in NMOSD patients. Our
findings indicate that serum PRX6 and PRX5 may be associated with
blood–brain barrier dysfunction in NMOSD, like pathological analyses in
patients with MS [13]. However, there was
no significant elevation in PRX levels within the CSF of MS and NMOSD
patients. Further studies are needed to confirm the definite mechanism
of PRXs in patients with MS and NMOSD.
Conversely, there is a limited number of papers regarding the role of
PRXs in EAE. It has been reported that mRNA levels of PRX1, PRX3, and
PRX6 were increased in the spinal cords of EAE mice compared with that
of control mice. Also, PRX6 was strongly expressed on cells with
astrocyte-like morphology in EAE lesions
[13]. PRX6-transgenic EAE mice exhibited
less severe pathology, which indicates that the upregulation of
astrocytic PRX6 has an important role in inhibiting the destruction of
myelin via microglial activation, blood–brain barrier breakdown, and
immune cell infiltration [13]. Similar to
pathological analyses in patients with MS
[13], upregulated PRXs inside astrocytes
may protect blood–brain barrier function and inhibit CNS inflammation.
Contrariwise, PRXs have an opposite face: having the ability to induce
inflammatory cytokines production as inflammatory mediators
[12]. In our study, only PRX5 was
upregulated in CD45+ cells (likely monocytes), which had infiltrated
into the spinal cord lesions of EAE mice. We speculate that CD45+ cells
may accumulate in the lesion and amplify the inflammatory response via
PRX5. Another possible explanation is that CD45+ cells were dealing with
ongoing oxidative stress. Although previous papers described the
upregulation of astrocytic PRX6 in EAE
[13], we did not observe the expression
of PRXs in astrocytes.
Some limitations of our study need to be addressed. First, increased
PRXs levels were not confirmed in the CSF but only the serum from
patients with MS and NMOSD. The small sample size in our study may
explain this discrepancy between serum and CSF levels of PRXs. Also, it
is still unclear as to which cells secreted PRXs into the serum.
Additional basic research studies are required to determine the source
of these PRXs. Finally, our pathological findings of EAE were different
from previous reports; EAE spinal cords showed PRX5 expression in CD45+
infiltrating cells but no PRX expression in astrocytes. One possible
explanation for this discrepancy is species-specific differences between
humans and mice. It is also possible that pathological characteristics
may differ according to disease status. Further studies are needed to
confirm the definite mechanism between PRXs and EAE pathogenesis.
From our results, we suggest that the elevations of serum PRX5 and PRX6
levels were associated with the pathogenesis of MS and NMOSD and
partially responsible for blood–brain barrier dysfunction in patients
with NMOSD. We also showed that upregulated PRX5 in CD45+ infiltrating
cells amplify inflammation in EAE. In summary, the expression of PRXs
was significantly altered in CNS inflammatory demyelinating diseases,
which suggests that they may trigger of blood–brain barrier disruption
or CNS inflammation. Consequently, the development of new treatment
targeting PRXs may reduce symptoms of MS and NMOSD.