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Microglial activation in the frontal cortex (Hannestad et al.,
2013; Bloomfield et al., 2016a, 2016b; Li et al., 2018), anterior cingulate cortex (Holmes et al., 2016, 2018; Su et al., 2016; Richards
et al., 2018; Setiawan et al., 2018), temporal cortex (Hannestad
et al., 2013; Bloomfield et al., 2016a, 2016b; Li et al., 2018;
Setiawan et al., 2018), and hippocampus (Doorduin et al., 2009;
Li et al., 2018; Setiawan et al., 2018) were observed in both MDD
and SCZ. However, the level of microglial activation differed between MDD and SCZ in some regions of the brain, such as the
prefrontal cortex (Holmes et al., 2018; Setiawan et al., 2018), insula (Holmes et al., 2016; Setiawan et al., 2018), total grey matter
(Bloomfield et al., 2016a, 2016b), and dorsolateral prefrontal
cortex (Holmes et al., 2016). Additionally, another PET study
revealed that TSPO binding in the middle frontal gyrus of SCZ
patients tended to be lower compared with those of matched
control participants (Notter et al., 2018). Therefore, such regional
differences in microglial activation might be crucial in defining
each psychiatric disorder.
In this study, the levels of MMP-7 and -10 in CSF were detectable at a low level. In past studies, MMP-7 and -10 were
normally undetectable or present at a low level in CNS (Yong
et al., 2001; Yong, 2005), which corresponds to this study. In
addition, the levels of MMP-7 and -10 in CSF were elevated
in MDD but not SCZ. In comparison, they were positively correlated with MMP-2 levels in both MDD and SCZ. MMP-7 is
secreted from microglia (Burke, 2004) in response to TNF-α
(Wang et al., 2018), which suggests that the elevated levels of
MMP-7 may reflect neuro-immune activation (Conant et al.,
1999). Although the role of MMP-10 in CNS remains unclear,
some past studies showed that MMP-10 activates pro-MMPs
(Sbardella et al., 2012). In addition, MMP-10 is also secreted
from microglia (Molin et al., 2017) and activates MMP-7
(Murphy et al., 1991), which in turn activates MMP-2 (Barille
et al., 1999). These findings and past studies suggest a potential inflammatory cascade, including an interaction among
MMP-2, -7, and -10, which might be activated in patients with
MDD. Therefore, further investigation of this inflammatory
cascade among MMP-2, -7, and -10 is expected to contribute
to elucidating the pathophysiology of MDD.
Activated microglia secretes numerous pro-inflammatory
cytokines (Gottschall et al., 1995; Lee et al., 2014; Mondel li
et al., 2017; Pan et al., 2018), which are differentially expressed
depending on each disorder, such as an elevated expression
of TNF-α in MDD (Enache et al., 2019) and that of IL-8 in SCZ
(Orlovska-Waast et al., 2019). In addition, TNF-α induces the expression of MMP-7 (Li et al., 2017) and MMP-10 (Pedersen et al.,
2009), which may explain why elevated levels of MMP-7 and
MDD-10 were observed in patients with MDD but not SCZ.
This study also showed that the levels of TP, an indirect
marker of brain inflammation (Orlovska-Waast et al., 2019), were
higher in the CSF of both patients with MDD and SCZ compared
with HC, which is consistent with a previous meta-analysis of
inflammatory markers levels in CSF of patients with MDD and
SCZ (Orlovska-Waast et al., 2019). This study also found a correlation between the levels of TP in CSF and depressive symptoms
as well as between the levels of MMP-2 in CSF and depressive
symptoms. Meanwhile, there was no correlation between TP
levels in CSF and schizophrenic symptoms. Therefore, the increased levels of MMP-2 and TP may reflect the occurrence of
neuroinflammation in MDD and SCZ. MMP-2 and TP may be inflammatory markers of both MDD and SCZ and simultaneously
be state markers of MDD.
This study has several limitations. First, because of the
limited CSF volume, it was not possible to measure CSF cytokine
Omori et al. | 7
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