1. Introduction
Schizophrenia is an incapacitating mental disorder
whose etiology is multifactorial. Within this context, both genetic
and environmental factors contribute to its occurrence (1). Following adversities in life (2,3),
gene-environment processes (3) and
epigenetic changes (4,5) may affect the expression of genes
implicated in synaptic function, neurodevelopment and stress
response. Such factors could potentially promote the occurrence of
schizophrenia through their effects on neurotransmitters and the
immune system, resulting in oxidative stress (6,7).
Genetic vulnerability in combination with prenatal and perinatal
risk factors (including maternal stress, viral infection,
malnutrition, zinc deficiency and hypoxia) may increase the
susceptibility to environmental stressors (such as childhood abuse,
urbanicity, migration and substance abuse) (8,9).
Similarly, it has been proposed that early-life adversity may alter
the hypothalamic-pituitary-adrenal axis function, leading to a
modified stress response and increased stress sensitivity to
potential stressors in adolescence and adulthood (9-11),
thus advancing the occurrence of schizophrenia symptoms through
dopaminergic hyperactivity (12).
Furthermore, prolonged exposure to stress and to glucocorticoids
may result in a reduction in hippocampal volume (13) and decreased levels of brain-derived
neurotrophic factor (BDNF) in patients with schizophrenia (14-19).
Despite causing major disability worldwide, and the
intense research performed over the last decades on the
investigation of the molecular mechanisms underlying schizophrenia,
its pathophysiology remains not fully understood. Numerous
questions regarding the dysregulated signaling pathways and the
molecular basis of differential personalised responses to various
treatments remain unanswered. The importance of genetic risk
factors and key cell signaling pathways is now confirmed; however,
further research is required to fully delineate the underlying
molecular mechanisms. Among the signaling pathways in schizophrenia
that show dysregulation is the Janus kinase/signal transducer and
activator of transcription (JAK/STAT) pathway, a pleiotropic
pathway that plays a key role in multiple cellular functions
(20-22).
Since its discovery >30 years ago, JAK/STAT represents one of
the most conserved pathways that transmits extracellular signals
from over 50 cytokines, growth factors and hormones, to the
nucleus, to tightly regulate target gene transcription (23,24).
The specific JAK/STAT-dependent expression programs define
important cellular responses linked to cell growth, proliferation,
cell cycle progression, development, apoptosis, differentiation,
migration, survival and malignancy (both solid and hematologic).
Furthermore, JAK/STAT plays a pivotal role in immune, inflammatory
and stress responses. The family of JAK kinases is composed of four
members (JAK1, JAK2, JAK3, and TYK2), while the STAT family in
mammals consists of seven members (STAT1, STAT2, STAT3, STAT4,
STAT5A, STAT5B, and STAT6). All STATs contain a conserved structure
that includes the N-terminal, the coiled-coil, the Src-homology 2
(important for STAT dimerization), the linker, the DNA-binding and
the transactivation domains (21).
The JAK/STAT pathway plays a key role in
inflammation, cancer and neurodegenerative diseases (25). Its importance for brain disorders
highlights the necessity to elucidate how it influences the
functionality of neural cells. In the present review, insights into
the dysregulation of the JAK/STAT signaling pathway in neurological
dysfunction and schizophrenia are provided. Inflammation and
signaling dysregulation, the crosstalk of non-coding RNAs (ncRNAs)
with JAK/STAT, the involvement of the JAK/STAT pathway in patient
stratification, management and treatment strategies, and
models/approaches to study signaling and to improve therapeutic
delivery of drugs in schizophrenia are discussed.
2. Methods
Searches across online databases, including PubMed,
Google Scholar and Web of Science, were performed by employing
specific keywords and their combinations [including JAK/STAT,
signaling, schizophrenia, neurological dysfunction,
inflammation/neuroinflammation, stress, ncRNAs (miRNAs, lncRNAs),
biomarkers, therapies, organoids, nanotechnology] to identify
publications relevant to this brief review. Due to space
limitations, not all publications have been included. For efficient
organisation, management and storage of the selected references,
Zotero version 7.0.26, developed by the Corporation for Digital
Scholarship, was used.
3. Inflammation and dysregulated signaling
in schizophrenia
Various cell types mediate innate immunity, which
participates in the defense of the immune system to various
pathogens and is connected to the tightly controlled action of
numerous signaling pathways, including the interferon (IFN),
mitogen-activated protein kinase, JAK/STAT, interleukin (IL),
chemokine receptor, and glycogen synthase kinase pathways. JAK/STAT
is considered important in regulating inflammatory and
immunological responses, thus promoting neuroinflammation in
neurodegenerative diseases (25).
Alterations to immune function have also been detected in
psychosis, with increased proinflammatory cytokines in the serum of
the patients, indicating activation of immune-related cells in the
circulation (26).
Inflammation is considered a key factor for the
onset and maintenance of schizophrenia, with a variety of cytokines
being dysregulated depending on the disease stage (27-29).
Cytokines, as key molecules of the immune system, control the
brain/nervous system response to exogenous insults and mediate the
communication of the nervous and immune systems (30). Cytokine imbalance has been detected
in both blood and cerebrospinal fluid of patients with
schizophrenia, particularly in T helper type 1 and type 2
cytokines, despite contradictory results in the literature
(31). Infections, autoimmune
diseases, and genetic predisposition are considered risk factors
for schizophrenia. Furthermore, chronic stress is reported to
contribute to a continued proinflammatory state that potentially
promotes the disorder (31).
4. Dysregulated JAK/STAT signaling in
neurological dysfunction and schizophrenia
JAK/STAT pathway in neurological
dysfunction
Dysregulated cytokines bind to receptors that
activate the JAK/STAT pathway, and thus are implicated in
neuropsychiatric disorders through numerous processes, including
neurogenesis, gliogenesis, synaptic plasticity and microglia
activation (32,33). JAK/STAT signaling is reported to be
linked with neurodegenerative and neuropsychiatric disorders. For
example, JAK/STAT is reported to regulate many of the genes
associated with epilepsy syndromes. Neurons respond to prolonged
BDNF exposure, both in vivo and in vitro, by
activating the JAK/STAT pathway. RNA-sequencing of neurons exposed
to BDNF, in the presence or absence of JAK/STAT inhibitors, showed
that the neuronal BDNF-induced JAK/STAT pathway involves more than
just STAT3 phosphorylation, supporting an underlying non-canonical
JAK/STAT mechanism (34).
Furthermore, STAT3 plays an important role in neural function
relevant to behaviour in both healthy and pathological conditions
(35). However, numerous questions
remain to be answered on STAT3 involvement in psychopathological
neural mechanisms. Knockdown approaches suggested that STAT3 in the
nuclei of the dorsal raphe (located in the midbrain and pons)
controls behavioural reactivity, and serves as a functional
connecting molecule between the upstream activators of STAT3,
serotonergic neurotransmission and psychopathology (35). The JAK/STAT/Rho-associated
coiled-coil containing protein kinase (JAK/STAT/ROCK) signaling
pathway has been linked to lung-brain-related immune responses.
JAK/STAT/ROCK is reported to be important for the crosstalk between
uncontrolled inflammation following upper respiratory tract
infections and the development of neurodegenerative diseases,
providing novel avenues for the therapeutic management of the
associated inflammation (36).
Based on such findings, it cannot be excluded that similar
mechanisms might exist in schizophrenia.
JAK/STAT pathway in schizophrenia
The JAK/STAT1 gene expression signature has been
downregulated in early psychosis and in individuals with an acute
exacerbation of psychosis who require hospitalisation. By contrast,
this specific expression signature was normalised in individuals
with longer psychosis duration and chronic psychopathology
(26). Such findings validate the
importance of the JAK/STAT pathway in neurophysiological circuits
that are critical for the development of psychiatric diseases,
including schizophrenia.
Stress triggers inflammation through the JAK/STAT
pathway, leading to neuroinflammation that causes neuronal and
synaptic dysfunction, and also cognitive impairments, which are
hallmarks of schizophrenia and other stress-associated
neuropsychiatric disorders. Cytokines released during the stress
response regulate gliogenesis, neurogenesis, and synaptic
plasticity. Chronic stress sustains JAK/STAT activation, leading to
the chronic inflammation observed in schizophrenia (37).
Furthermore, a single-nucleotide polymorphism (SNP)
in the ZNF804A gene has been associated with decreased
transcript levels in the fetal brain and has been linked to
schizophrenia and bipolar disorder. The formation of a protein
complex of ZNF804A with IFN-activated STAT2 has indicated its
function as a signal transducer that activates IFN-mediated gene
expression programs, which are important for schizophrenia
pathophysiology (38). Activation
of STAT1 by signaling cascades initiated by receptors triggered by
proinflammatory cytokines (such as IFNγ, IL-6, IL-2, IL-10),
hypoxia, infections and peptide growth factors has also been
reported to be dysregulated in schizophrenia (39). Such findings confirm the implication
and importance of the dysregulated pleiotropic JAK/STAT pathway in
schizophrenia, which influences several key disease-related
cellular functions (Fig. 1).
 | Figure 1Dysregulation of JAK/STAT signaling
pathway and other cellular functions in schizophrenia. The
schematic diagram of the JAK/STAT signaling pathway is shown in the
middle. The normal condition is depicted on the left, where no
dysregulation is observed in the JAK/STAT pathway, and the cellular
functions controlled by the JAK/STAT pathway (including
inflammation, immune regulation and response, hematopoiesis,
apoptosis, differentiation, proliferation, metabolic actions, cell
cycle, and transcriptional and epigenetic regulation) are in
homeostasis. In schizophrenia (on the right), upon dysregulation of
the JAK/STAT and other pathways, metabolic, transcriptional and
epigenetic dysregulation, chronic stress, depression,
neurodegeneration, neuronal dysfunction and apoptosis, synaptic
loss, inflammation and dysregulated ncRNAs are observed. JAK/STAT,
Janus kinase/signal transducer and activator of transcription;
ncRNA, non-coding RNAs. The figure was created using BioRender
(https://BioRender.com). |
5. Crosstalk of ncRNAs with the JAK/STAT
pathway in schizophrenia
ncRNAs hold key roles in regulating gene expression
and have been linked to neurological and neuropsychiatric
disorders, including schizophrenia. ncRNAs regulate inflammation,
and pro- and anti-inflammatory factors are regulated by microRNAs
(miRNAs or miRs). Long ncRNAs (lncRNAs) also affect miRNAs
(40). Dysregulation of ncRNAs in
schizophrenia has been reported, with studies showing altered miRNA
expression (including miR-132, miR-212, miR-34a/miR-34c, miR1307)
and lncRNA changes in brain tissues from patients with
schizophrenia (41,42). Among others, Gomafu, PINT, GAS5,
IFNG-AS1, FAS-AS1, PVT1, and TUG1 have been reported as
downregulated lncRNAs in schizophrenia. By contrast, MEG3, THRIL,
HOXA-AS2, Linc-ROR, SPRY4-IT1, UCA1, and MALAT1 have been reported
as upregulated. Furthermore, miR-30e, miR-130b, hsa-miR-130b,
miR-193a-3p, hsa-miR-193a-3p, hsa-miR-181b, hsa-miR-34a,
hsa-miR-346, and hsa-miR-7 have been shown to be dysregulated in
blood or brain samples of patients with schizophrenia (43). Despite all these findings, the
evidence for a crosstalk between ncRNAs and the JAK/STAT pathway in
schizophrenia and other neuropsychiatric disorders is currently
limited. ncRNAs can regulate JAK/STAT signaling by acting as
downstream or upstream modulators (44). The lncRNAs AC006129.1 and
RP5-998N21.4 are involved in immune responses and interact with
pathways such as JAK/STAT, through the regulation of SOCS3 and
STAT1, respectively (44-46).
Extensive ncRNA crosstalk with JAK/STAT pathway
components is mainly documented in cancer (47). Evidence from neurological-related
and other tumors shows that certain ncRNAs can regulate the
JAK/STAT pathway by interacting with pathway regulators (such as
SOCS1) or by directly affecting the expression and activation of
JAK/STAT proteins, thereby influencing inflammation and cell
signaling (48,49). Our previous studies demonstrated
significant downregulation of specific miRNAs (let-7p-5p, miR-98-5p
and miR-183-5p) in patients with cancer only, and cancer with
schizophrenia, when compared to patients with schizophrenia only,
suggesting an oncosuppressive role for these miRNAs (50-52).
Based on our findings (50-52)
and the extensively studied crosstalk of ncRNAs with JAK/STAT in
various malignancies (53-57),
it cannot be excluded that similar crosstalk participates in
mechanisms that lead to schizophrenia, a hypothesis that needs
further exploration and validation in future studies.
6. JAK/STAT pathway in the therapeutic
management of schizophrenia
Given the importance of the JAK/STAT pathway in
neurodegenerative and neuropsychiatric diseases, the use of
JAK/STAT pathway components as biomarkers for monitoring disease
progression and response to therapies, or for therapeutic targeting
of schizophrenia and other relevant diseases, constitutes a
clinical necessity.
JAK/STAT components as biomarkers
Components of the JAK/STAT signaling pathway have
already been utilised as biomarkers of disease state. Patients with
schizophrenia with poorer cognitive performance have expressed
significantly higher levels of activated pSTAT1 when compared with
controls, providing a biomarker of biological significance
(39). Phospho-specific cell
signaling epitope expression in peripheral blood mononuclear cell
(PBMC) subtypes, in drug-naïve schizophrenia patients compared with
controls, has identified specific disease alterations. In
combination with serum immune response proteins, polygenic risk
scores, drug response and side effects, such alterations have been
analysed throughout the antipsychotic therapy. Among others, Stat3
(pS727), Stat3 (pY705) and Stat5 (pY694) across PBMC subtypes have
been linked with schizophrenia at disease onset, and have been
correlated with the type I IFN-related serum molecules CD40 and
CXCL11. Alterations in Stat3 (pS727), among other molecules,
predicted the development of metabolic and cardiovascular side
effects following antipsychotic treatment, together with side
effects and early improvements in general psychopathology scores
(58). Such findings validate the
importance of using PBMCs as a valuable model for detecting
intracellular signaling alterations in schizophrenia for
stratification of patients with differential clinical outcomes or
risk for side effects of antipsychotic treatment (58). Furthermore, highly sensitive
C-reactive protein, a biomarker for detecting inflammation in
schizophrenia (33), has been used,
and elevated levels of pro-inflammatory and anti-inflammatory
cytokines have been detected in the peripheral blood of patients
with first-episode schizophrenia and relapsed, when compared with
healthy controls. Specifically, IL-6, IL-1, TNF, and IFN have been
demonstrated to be dysregulated in schizophrenia (33). It cannot be excluded that such
findings may be linked to dysregulation of the JAK/STAT pathway or
can be used in combination with detected dysregulation of JAK/STAT
components or relevant ncRNAs for more accurate stratification,
therapeutic management, and prediction of therapeutic response in
schizophrenia.
JAK/STAT targeting for therapeutic
purposes
Anti-inflammatory agents inhibiting relevant
signaling pathways might serve as useful treatments for
inflammatory schizophrenia (33).
Such agents have been effective in reducing disease symptoms and
increasing the functionality of patients. Despite encouraging
results, further research is needed towards the personalised
approach of such treatments (33).
Small-molecule inhibitors of JAKs (jakinibs) have
been safe and efficient for the treatment of diseases with
underlying inflammation (rheumatoid arthritis, psoriasis, and
inflammatory bowel disease) (59),
and may constitute promising treatments for schizophrenia in the
future.
Symptoms of depression, frequent in schizophrenia,
and the antidepressant actions of current treatments have been
mediated by JAK/STAT-dependent mechanisms (60). Furthermore, inflammation and
oxidative stress have been targeted for the development of novel
therapies for depression. The finding that the JAK/STAT pathway
might mediate antidepressant-like effects of N-acetylcysteine,
suggests the importance of targeting this pathway for novel and
effective therapies for depression (60).
The pathogenesis of schizophrenia involves abnormal
activation of microglia. Minocycline and antipsychotics have been
effective in blocking the activation of microglia and thus reducing
the negative symptoms of schizophrenia. When microglia cells were
activated by lipopolysaccharide and treated with minocycline,
haloperidol, and risperidone, various effects were detected in
cytokine production and signaling pathway dysregulation.
Minocycline was shown to suppress JAK2 and STAT3 activation.
Risperidone and haloperidol only suppressed STAT3 activation. These
findings have shed light on the underlying mechanisms of
minocycline and atypical antipsychotics for the treatment of
schizophrenia (61) and indicated
the importance of targeting the JAK/STAT pathway.
Therapeutic agents that target the JAK/STAT pathway
involve cytokine or receptor antibodies, JAK inhibitors, and STAT
inhibitors, which have been applied to various cancers and
autoimmune diseases. Pimozide, an antipsychotic drug belonging to
the diphenylbutylpiperidine class, has been shown to inhibit the
action of STAT proteins, mainly STAT3 and STAT5(62). When pimozide was used to treat
schizophrenia, the patients demonstrated a lower incidence of solid
malignancies. Further studies have demonstrated that pimozide
induces apoptosis and decreases metastasis through mechanisms
involving STAT3, STAT5 and other molecules (63,64).
As inflammation plays a major role in the onset and maintenance of
schizophrenia, and the dysregulated cytokines depend on the phase
of the illness (33), a wide
variety of anti-inflammatory agents may inhibit subsequent pathways
and have been effective for treatment. Hormonal therapies,
antioxidants, omega-3 fatty acids, and minocycline have improved
symptoms and everyday functioning of the patients (33); however, many questions remain to be
answered on the crosstalk of such anti-inflammatory agents with the
JAK/STAT pathway. Furthermore, their action in other cellular
processes beyond inflammation requires further investigation and
questions their efficacy for the improvement of schizophrenia.
Current therapies to mitigate inflammation in schizophrenia also
include antibiotics and emerging biological agents that target
specific inflammatory pathways (27,61).
Additional strategies involve probiotics and advanced techniques,
such as nanotechnology, to effectively deliver therapeutic agents
(65). These are often used as
adjunctive medication, added to traditional treatments to improve
symptoms (65). The therapeutic
targeting of ncRNAs to reduce inflammation is also of importance,
as ncRNAs can serve as therapeutic targets in inflammation-related
diseases (40), including
schizophrenia.
It is expected that targeting the dysregulated
JAK/STAT pathway alone, or in combination with the already reported
anti-inflammatory therapies, or the ncRNAs regulating the JAK/STAT
pathway, will contribute to the development of efficient and
personalised therapeutic management approaches for
schizophrenia.
7. Models and approaches to study signaling
pathways in schizophrenia
Organoids
Organoid models of schizophrenia have been
successfully used to study dysregulated signaling pathways,
providing pioneering tools in understanding the underlying disease
mechanisms. Patient-derived induced pluripotent stem cell (iPSC)
organoids have been used. Such models in schizophrenia confirmed
dysregulation of signaling (FGFR1) that affects cortical
development (66), and
dysregulation of genes functionally relevant to synapses,
neurodevelopment, axonal guidance, synaptogenesis and other
pathways (67-69).
Such studies demonstrate the reliability of organoid models to
recapitulate signaling and other pathway disruptions in
schizophrenia. However, the study of the JAK/STAT signaling field,
using organoid models, remains unexplored. Research using organoids
is expected to address the role of JAK/STAT in schizophrenia in the
near future.
Nanotechnology
Nanotechnology describes various devices, carriers,
and materials that facilitate the transportation of drugs for
therapeutic purposes, and includes nanomaterials and nanodevices.
Nanotechnology, encompassing engineered small-scale objects that
match the sizes of biomolecules, their assemblies, and cellular
parts (70), provides unique
opportunities to understand brain functions. Nanomaterials, acting
as nano-sized lipophilic carriers, facilitate the transportation of
drugs across the blood-brain barrier (71). As an example, when miR-137, which
controls key cognitive and sensory processing genes that are
dysregulated in schizophrenia, was encapsulated in nanoparticles,
nontoxic delivery and easy incorporation into cells was achieved
(72). Nanopsychiatry aims to
improve agents for the treatment of psychiatric diseases through
the use of nanoscaled carriers. Devices capable of detecting levels
of dopamine and serotonin in patients, which could improve
schizophrenia diagnostics, have already been developed. Novel
nano-sized drug delivery systems, by increasing the efficacy and
pharmacokinetics of traditional schizophrenia drug treatments,
could improve the therapeutic landscape of this complex disease
(73). The use of nanotechnology
systems to study dysregulated signaling pathways, including
JAK/STAT in schizophrenia, is currently limited; however, it is
expected to expand in the near future and to improve the delivery
of drugs targeting JAK/STAT or other pathways for the therapy of
schizophrenia.
8. Conclusion
Schizophrenia, a traditionally defined brain
disorder, is now known to be controlled by the periphery and the
immune system. The JAK/STAT pathway plays a key role in
inflammation and neurodegenerative diseases. Its importance for
most brain disorders highlights the necessity to elucidate how it
functionally modulates molecular pathways in neural cells. In this
short review, insights into the dysregulation of the JAK/STAT
signaling pathway in schizophrenia are provided. Aspects of the
dysregulated signaling in inflammation, the cross-talk of ncRNAs
with JAK/STAT, the involvement of JAK/STAT in therapeutic
management strategies, and the models/approaches to study signaling
and to efficiently deliver treatments in schizophrenia are
discussed.
Future research on the dysregulated JAK/STAT
signaling pathway using organoid models will generate scientific
knowledge to further elucidate the pathophysiology of this complex
disorder. Additionally, it is expected to provide useful biomarkers
or therapeutic targets to develop novel and more efficient
stratification and therapeutic management strategies for
schizophrenia. Nanopsychiatry and nanotechnology are also expected
to improve the delivery of drugs targeting JAK/STAT or other
pathways towards efficient and personalised therapies for
schizophrenia.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
ER and EK wrote and edited the manuscript. CT, JNT
and DAS edited the manuscript. All authors contributed to the
article, and read and approved the final manuscript. Data
authentication is not applicable.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
DAS is the Editor-in-Chief for the journal, but had
no personal involvement in the reviewing process, or any influence
in terms of adjudicating on the final decision, for this article.
The other authors declare that they have no competing
interests.
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