The Potential Role of Toll-like Receptors in Schizophrenia: History
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Contributor:
Saahithh Redddi Patlola
,
Gary Donohoe
,
Declan P. McKernan

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) ubiquitously expressed in the human body. They protect the brain and central nervous system from self and foreign antigens/pathogens. The immune response elicited by these receptors culminates in the release of cytokines, chemokines, and interferons causing an inflammatory response, which can be both beneficial and harmful to neurodevelopment. Such changes due to TLRs are shown to be associated with alterations in cognitive functions in various neurodegenerative and psychiatric disorders, and schizophrenia is one such disorder where multiple genetic and environmental factors contribute to alterations associated with TLRs.

  • inflammation
  • Toll-like receptor
  • schizophrenia
  • cognition

1. Introduction

Schizophrenia is a debilitating psychiatric disorder affecting 0.45% of adults worldwide, according to the World Health Organisation, [1]. According to 2019 data, the prevalence of schizophrenia ranges from 0.2 to 0.5% across nations worldwide [2]. Emerging evidence suggests the role of the immune system and its various components in the risk of schizophrenia, including cytokines, C-reactive protein, chemokines, antibodies, etc. [3]. Multiple studies show altered protein and mRNA expression of Toll-like receptors (TLRs) in schizophrenia compared to healthy adults [4][5][6]. Human postmortem studies carried out on individuals diagnosed with schizophrenia, brain samples showed lower tlr4 mRNA and protein levels, and downregulation of il6, il10, and tnfa mRNA in the prefrontal cortex (PFC) region [7][8], and elevated TLR4 protein levels in the cerebellum region [7]. On the contrary, high tlr4 and myd88 mRNA expression was observed in the PFC region of the human brain [9]. On the flip side, studies on peripheral blood show downregulation of tlr3 and 5 mRNA levels and upregulation of il6 and il10 mRNA levels in patients with schizophrenia [10], which is in contrast to evidence from brain samples. Studies of acute and first-episode psychosis (FEP) patient groups reported higher expression (measured by mean fluorescence intensity (MFI)) of TLR3, 4, and 5, but not TLR2, in monocytes [11][12]. Although Keri et al. observed higher TLR4 MFI in schizophrenia post-TLR4 stimulation, the MFI expression of IL-6, TNF-α, and IL-1β was lower than controls [12]. Similar results were also observed by Muller et al. with IL-1β. This was interpreted to represent an increase in TLR expression to compensate for the functional deficit [11]. In contrast, whole blood stimulation studies in schizophrenia showed elevated concentrations of IL-6, TNF-α, and IL-1β post-TLR2 stimulation, and increased IL-1β alone post-TLR4 and 8 stimulation [13]. Individual blood cell studies in FEP patients showed lower TLR protein expression in monocytes, B cells, and T cells [6]. Overall, researchers can infer that dysregulation of TLR expression exists in patients with schizophrenia and varies at various stages of disease progression (Table 1), but researchers do not have sufficient evidence to implicate their extent of involvement in the immunopathology of schizophrenia.
The concept of immune-mediated risk for schizophrenia has existed since the late 1920s. The first instance of this was observed in the years following the Spanish flu pandemic, when some patients with influenza showed psychosis-like symptoms [14]. After this, the theory of virus-induced psychosis became popular (see [15] for more details), and many other infections from viruses, bacteria, and parasites were linked to the risk of schizophrenia, such as herpes simplex virus (HSV) [16], Epstein–Barr virus [17], and Toxoplasma gondii [18]. The most common theory about infections in relation to schizophrenia is related to the stimulation of the foetal immune system due to maternal infection, or by the antibodies generated by the mother in response to infection, ultimately posing a risk of schizophrenia in the offspring [19].
Table 1. Characteristics of human studies.
Study Diagnosis of Schizophrenia Sample type
TLR analysed
Analysis result
García-Bueno et al., 2016  DSM-IV.
Absence of other neuropsychiatric disorders and drug abuse.		 Post-mortem human
brain tissue
(PFC)
TLR4 and MyD88
protein and mRNA
expression
Significant higher TLR4, MyD88 not IkBa and NFkB protein expression in patients.
No change in MyD88 mRNA expression.
Significant higher TLR4, MyD88 not IkBa protein expression & MyD88 mRNA expression in patients treated with anti-psychotics Vs Controls.
Significant higher NFkB protein expression in anti-psychotic free patients Vs Controls.
López-González et al., 2019 DSM-IV and ICD-10.
No history of neurological diseases.		 Post-mortem human
brain tissue
(PFC)
TLR4 and TLR7
mRNA expression
Significant downregulation of TLR4 not TLR7 in patients
MacDowell et al., 2017 DSM-IV and ICD-10.
No history of neurological diseases.		 Post-mortem human
brain tissue
(PFC & CB)
TLR4 and MyD88
protein expression
Significant lower TLR4, MyD88 and IkBa, not NFkB in patients (PFC)
Significant higher TLR4, MyD88 and IkBa, not NFkB in patients (CB)
Chase et al., 2019 SCID-IV.
No current or previous psychiatric history.		 PBMC
TLR4 mRNA expression
Adverse childhood events were associated with IL-6 expression but not TLR4.
Juncal-Ruiz et al., 2020 DSM-IV.
Absence of other neuropsychiatric disorders and drug abuse.		 PBMC
TLR1-9 protein
expression
FEP patients showed significantly higher TLR1 but not TLR 5 & 8 in PBMCs.
3 months of anti-psychotic treatment led increase in TLR6 monocyte expression and a similar trend for TLR8 & 9 in PBMCs.
Kozłowska et al., 2019 DSM-IV and ICD-10.
No history of neurological diseases.		 PBMC
TLR1-9 mRNA
TLR1,2,4,6 & 9 expressions were downregulated in patients
TLR3 & 7 expressions were upregulated in patients
TLR5 & 8 no change
Chang et al., 2011 Patients were recruited
if they experienced psychosis (hallucinations or delusions).		 Monocytes
TLR1-6 & 9 mRNA
expression
Downregulation of TLR3 & 5 mRNA in patients. No change with other TLRs
Kéri et al., 2017  SCID-CV.
No current or previous psychiatric history.		 Monocytes TLR1,2,4,5 &6
protein expression		 Significant higher TLR4 &5 expression in patients.
At baseline TLR4 & 5 expression correlates with RBANS scores but not post-medication.
Li et al., 2022 DSM-IV.
Absence of other neuropsychiatric disorders and drug abuse.		 Monocytes TLR4 protein expression Elevated TLR4 was associated with decreased processing speed and social cognition.
Li et al., 2022 DSM-IV.
Absence of other neuropsychiatric disorders and drug abuse.		 Monocytes TLR4 protein expression Elevated TLR4 was associated with decreased reasoning/problem-solving and MCCB scores in schizophrenia patients with tardive dyskinesia but not with no tardive dyskinesia or controls.
Müller et al., 2012 DSM-IV. Monocytes stimulated
with poly (IC), LPS		 TLR2, 3 & 4
protein expression		 no change with TLR2
Significant higher TLR3 in patients Vs controls (unstimulated and PolyIC); no changes in LPS stimulated.
Significant higher TLR4 in patients Vs controls (unstimulated); no changes in LPS and polyIC stimulated.

Characteristics of Human studies illustrating TLRs in various models and cognition. PFC—prefrontal cortex, CB—cerebellum, PBMC—peripheral blood mononuclear cells, LPS—lipopolysaccharide, TLR—Toll-like receptor, RBANS—Repeatable Battery for the Assessment of Neuropsychological Status, MCCB—Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS™) Consensus Cognitive Battery, MyD88—myeloid differentiation primary response 88, NFkB—nuclear factor kappa B, IkBa—, poly (IC)—polyinosinic:polycytidylic acid, LPS—lipopolysaccharide, DSM-IV—Diagnostic and Statistical Manual of Mental Disorders-IV, SCID-CV—Structured Clinical Interview for DSM-Clinical version, ICD-10—International Classification of Diseases-10.

2. Maternal Immune Activation (MIA) and Early Life Exposure

Increased risk for psychosis-like symptoms following MIA (inflammatory stimuli due to TLR activation), conventionally associated with increased production of cytokines and chemokines, in offspring has been theorised for a long time [20][21]. Infections such as cytomegalovirus, influenza, herpes simplex virus, and coronavirus lead to upregulation of TLR mRNA (2–4 and 7–9). This is also accompanied by an increase in interferon and cytokine production causing complications in pregnancy, miscarriage, or foetal abnormalities [22][23]. These elevated cytokines and chemokines can migrate from the placenta into the foetus, and such exposure could cause changes to the CNS, leading to abnormal neurodevelopment [24]. Moreover, conditions such as diabetes mellitus, obesity, and systemic lupus erythematosus (SLE) in pregnancy were linked to high expression of TLRs, cytokines, and chemokines in peripheral blood, and similar levels were reflected in the placenta [25][26][27]. This suggests that conditions other than viral/bacterial stimuli could lead to an elevation in proinflammatory cytokines that could cross the placenta leading to prenatal immune activation increasing the risk of schizophrenia.
One of the earliest epidemiological studies linking infection with schizophrenia was in 1989, which was based on the data of subjects born during the epidemic period (1918 and 1957 influenza epidemic) reporting schizophrenia. A significant risk (1.4 risk ratio) of schizophrenia was observed in the subjects whose mothers were exposed to infection during 5–7 months of pregnancy compared to other months of pregnancy in the Scottish population. The same was not observed if all United Kingdom subjects were considered [28]. Similarly, another study conducted on patients diagnosed with schizophrenia showed that the risk of schizophrenia greatly increased in offspring with elevated maternal antibodies against type 2 HSV infection during pregnancy [16]. Despite the small sample size (N = 27/50 case/controls), it was reported that elevated maternal serum TNF-α during pregnancy had an association with the risk (8.5 odds ratio (OR)) of schizophrenia later in their offspring [29]. Animal models show that neural progenitor cells (NPCs) (NPCs undergo multiple changes to develop into neurons) expressed TLR3 and IRF3, and these cells responded to both in vitro and in vivo (dams) stimulation with poly I:C. Although conflicting results were observed from both models, in vivo results showed a significant decrease in cell proliferation post-treatment [30]. Similarly, irregular differentiation (high cholinergic neuronal differentiation and undifferentiated progenitors) and neurodevelopment were observed when forebrain from rat embryos were cultured with microglial conditioned medium stimulated by LPS [31]. Such evidence points to the detrimental neurodevelopmental effects on the foetus during pregnancy postexposure to infections or stimuli (TLR ligands), which could later affect the offspring.
For a long time, TLRs have been considered a target for vaccine adjuvants to increase the efficacy of the vaccine, where they act by low-level stimulation of the target TLRs and activate the interferon pathway [32]. It was observed in animals that vaccination for influenza promoted better neural development (indicated by increased cell proliferation, neural differentiation, and expression of brain-derived neurotrophic factor (BDNF) in pups) and provided protective function in the mother and offspring through TLR4 stimulation [33]. The aforementioned evidence indicates that the extent of activation of TLRs is determined by the severity of the infection in mothers, further affecting the neurodevelopment in the offspring while appropriate care such as vaccination, where the virus cannot replicate, can promote protective effects through TLRs on the offspring.
Animal models show a more detailed picture of MIA (Table 2). Intraperitoneal administration of Poly I:C and LPS in dams led to upregulation of TLR3 and 4 mRNA expression in the hippocampus tissue of the offspring. Moreover, this upregulation was associated with sociocognitive deficits and behaviour abnormalities in them [34]. In another study, post-LPS treatment in dams, mice showed upregulation of TLR2 and 4 mRNA in addition to COX-2 (cyclooxygenase), iNOS (inducible nitric oxide synthase), and CCL2 (chemokine C-C motif ligand) in the foetal stage, and later in adolescence. This was suggested to affect the microglial and astrocyte development in the amygdala region of the brain [35].
Table 2. Characteristics of animal studies.
Study Animal
(Type of Cells/Culture)		 Model TLR Analysed Analysis Results
Talukdar et al., 2021 [34] Rats MIA (Poly IC and LPS) TLR2, 3, and 4 mRNA Elevated TLR genes were highly associated with a decrease in sociability and normal behaviour in the offspring.
Lee et al., 2016 [36] Mice MIA (Zymosan) TLR2 TLR2 stimulation showed decreased cognitive and behavioural changes only in female offspring.
O’Loughlin et al., 2017 [35] Mice MIA (LPS) TLR2 and 4 mRNA Elevated TLR genes in pre/postnatal stages after stimulation.
These were associated with morphological changes in microglia, suggesting activation.
Connolly et al., 2021 [37] Mice TLR 4 antagonism TLR4 TLR4 antagonism showed beneficial cognitive effects
(enhanced spatial learning and memory) only in young female mice.
Drouin-Ouellet
et al., 2012 [38]		 Mice MyD88 KO TLR The absence of MyD88 in mice led to spatial learning and working memory deficits, and reduced motor activity.
Ibi et al., 2009 [39] Mice Poly IC stimulation TLR3 TLR3 stimulation showed decreased social interaction, cognitive, and behavioural changes.
Liu et al., 2013 [40] Mice TLR7 KO TLR7 TLR 7 activation reduced dendrite growth mediated by IL-6 in mice.
TLR 7 KO reduced dendrite growth and reduced behavioural activity.
Madar et al., 2015 Mice TLR2 KO and TLR2+ TLR2 TLR2 KO decreased mice activity and impaired spatial learning. Neonatal TLR2/1 activation led to impaired spatial learning in adulthood.
Park et al., 2015 Mice TLR2 KO TLR2 TLR2 KO mice showed cognitive and social recognition impairment.
Melnik et al., 2012 Mice In utero (poly IC stimulation) TLR3 mRNA TLR3 stimulation leads to decreased proliferation after Poly IC treatment unlike, in vitro studies.
Mice
(DG NPC)		 Poly IC treatment TLR3 mRNA TLR3 stimulation leads to increased proliferation after 24 and 48 h of poly IC treatment.
Liu et al., 2013 [40] Mice
(cortical neurons)		   TLR 7 TLR7 activation produced cytokines and hindered dendrite growth. TLR7 KO promoted axon and dendrite growth.
Nakajima et al., 2014 [41] Mice
(astrocyte cell culture)		 LPS stimulated TLR3 and 4 mRNA LPS stimulation showed significantly elevated TLR3 expression up to 24 h and dropped until 72 h.
No significant change was seen with TLR4 expression, but a trend of upregulation was observed from 3 to 72 h.
Zhou et al., 2020 [42] Mice
(BV2 microglial cells)		 LPS treatment TLR4 protein TLR4 and NF-kB upregulation post-treatment.
Characteristics of animal studies showcasing the effect on TLRs in various models and cognition. DG-NPC—Dentate gyrus-neural progenitor cells, LPS—lipopolysaccharide; TLR—Toll-like receptor, MIA—maternal immune activation, KO—knockout, IL-6—interleukin-6.
Similar to the MIA model, exposure to harmful environmental stimuli during childhood or early stages of life can affect neurodevelopment, cognitive functions, and behaviour [43][44]. Such dysfunction later in life contributes towards the risk of psychosis/schizophrenia. A meta-analysis on early exposure to CNS infections showed that childhood exposure to viral, but not bacterial, infections led to twice the risk of schizophrenia during adulthood [45]. It was also observed in neonatal mice studies that an increase in tnfa mRNA and impairment in behaviour and memory resulted after repeated exposure to poly I:C (TLR3 agonist) for 5 days. Additionally, disruption in glutamatergic neurons in the hippocampus (responsible for learning and memory) was observed [39]. When neonatal rats were administered poly I:C intraperitoneally, reduced white matter density and slow myelin development were observed. Moreover, 12 weeks post-treatment, elevation of tnfa and downregulation of bdnf, arc (activity regulated cytoskeleton associated protein), and egr1 (early growth response 1) mRNA (associated with neurodevelopment) in the hippocampus was observed, resulting in poor memory, motor activity, and coordination [46][47]. One of the recent studies demonstrated that, in patients with schizophrenia having exposure to childhood trauma, IL-6 played a role in mediating the biological events leading to social cognitive deficits [48]. Similarly, IL-6 was reported to mediate the development of internalising symptoms (anxiety, depression, and social withdrawal) in children after experiencing an adverse event [49]. Interesting findings from Chase et al. showed an increased expression of il6 mRNA in the schizophrenia group, without any significant changes in tlr4 mRNA expression. Furthermore, there was a significant decrease in ifng and irf1 mRNA expression [5]. This indicates that the increase in il6 mRNA expression could be due to other TLRs or other pattern recognition receptors (PRRs). The downregulation of interferons was probably due to the TLR4/IRF1-dependent pathway, as observed in macrophages [50]. Another possibility could be that there was an increase in TLR activity without any change in its expression.

3. Factors Influencing Toll-like Receptors in Schizophrenia

3.1. Diet and Gut Microbiome

There are many diseases and disorders that are associated with improper diet. Studies showed that prenatal malnutrition during famine throughout the world in various eras increased the risk of nervous system-related disorders and mental illnesses such as schizophrenia, antisocial behaviours, other psychiatric disorders, and congenital anomalies such as neural tube defects [51]. Although it is unclear if this was due to the direct result of malnutrition (diet change) or other underlying causes such as stress, it was observed in Dutch and Chinese populations who experienced the ‘Dutch hunger of 1944–1945’ and ‘Great leap forward of 1958–1962’, respectively, that the risk of acquiring mental illness, especially schizophrenia, was two-fold higher in the populations born during these great famines [51][52].
Similar to how dietary deficits can be dangerous to mental health, an imbalanced diet lifestyle can affect the same. The nutritional psychiatry division of Harvard reports that the type of food can affect the inflammatory status and oxidative stress in the body. It was observed that the traditional diet from Asian and Mediterranean areas proved to have a 25–30% lower risk of depression when compared to the western diet [53]. Moreover, studies show that saturated fatty acids (SFAs) are capable of activating microglia and inducing proinflammatory cytokines, which is facilitated by TLR2 and 4 [54]. The mRNA levels of il6, il1b, and tnfa were found to be elevated post-SFA treatment in mouse cell culture, and their upregulated expression was similar to that of LPS stimulation [55]. Furthermore, in in vitro studies (mouse and human), TLR2- and 4-dependent activations were observed with SFAs. TLR2, 3, 5, and 9 activations by their respective agonists were attenuated by ω-3- and ω-6-polyunsaturated fatty acids (PUFAs), indicating that some fatty acids activate TLRs, and some others inhibit their activity [54][56][57].
A high-fat diet is closely related to obesity [58], and it was observed that a high-fat diet elevated proinflammatory cytokine expression via the TLR pathway (NF-kB activation), causing an inflammatory state which correlated with weight gain [59][60]. This high-fat diet can also dysregulate the gut microbiome [61], due to bacterial metabolites migrating to the brain and crossing the BBB [62], and inducing inflammatory responses in the brain. This further affects neurodevelopment (discussed in detail elsewhere [63][64]). The “leaky gut” MIA model suggests that metabolites from maternal microbiome dysbiosis can act as inflammatory stimuli on the foetus [64] and, in turn, potentially increase the risk of psychiatric disorders such as schizophrenia.
Evidence also suggests that the presence of unwanted or harmful microbes such as Saccharomyces cerevisiae (induced gastrointestinal inflammation) is associated with schizophrenia in both FEP and chronic patients [64][65]. Furthermore, schizophrenia was found to be associated with gastrointestinal dysfunction symptoms. The prevalence rate of such symptoms and conditions such as irritable bowel syndrome is higher (~19%) in these patients over healthy individuals [66]. This suggests that the microbiome and diet might have a role in the immunopathology of schizophrenia.

3.2. Drugs

Antipsychotic drugs or neuroleptics have both intended (therapeutic) and unintended (adverse/side effects) effects. For instance, the antipsychotic drug clozapine’s main target is dopamine and serotonin receptors, and this interaction leads to the alleviation of positive and negative symptoms in many patients. In addition, it acts partially on muscarinic, adrenergic, and histamine receptors, which leads to side effects such as drowsiness and dizziness [67]. Similarly, there is a vast literature that implicates antipsychotic medication as having another function, which is to alter the cytokine network in the schizophrenia population [68][69][70][71]. It is not yet understood how this medication alters cytokine levels, but researchers can hypothesise two possibilities: Firstly, they could affect the cytokine levels directly by unknown means, or they alter the TLR expression/protein levels and regulators in their downstream signalling, further influencing the cytokine expression. It could possibly be the latter, as TLRs regulate cytokine expression. In congruence with this statement, a study showed that paliperidone [72] and clozapine [73] reduced the inflammatory response (LPS-induced) associated with TLR4 by partly inhibiting the calcium/calmodulin-dependent Akt (protein kinase B) in a rat microglial cell line. Inhibition of this enzyme prevents Akt-dependent IKKα phosphorylation, further preventing NF-kB nuclear translocation [73]. Moreover, the MIA model of mice using poly I:C reported that paliperidone prevented the upregulation of TLR3 protein in the frontal cortex region [74]. On the contrary, another antipsychotic treatment, olanzapine, resulted in a significant rapid elevation of inflammatory cytokines (IL-6, TNF-α, IL-1β) and TLR4 protein expression in rat PFC [75]. A study on unmedicated patients reported significantly higher expression (MFI) of TLR2 in monocytes post-antipsychotics treatment, whereas TLR4 and 5 MFI were significantly higher before medication, and no difference after [76]. These studies indicate that drugs alter TLR downstream signalling, which leads to cytokine imbalance. On the other hand, studies reported that antipsychotic-treated patients showed higher expression of tlr4 mRNA [9][77] and myd88 mRNA [9] in peripheral blood and postmortem brain tissue samples, respectively, over antipsychotic-free patients (schizophrenia). Interestingly, no significant differences were observed in the other downstream signalling protein mRNA levels such as nf-kb, ikbα, il-1β, and il-6 [9]. On the other hand, 3 months of antipsychotic treatment resulted in higher TLR6 protein expression, and a trend towards higher TLR8 and 9 in monocytes, T cells, and B cells of FEP patients [6]. Given the evidence, there is a disparity in the current literature regarding the influence and relationship between antipsychotic drugs and TLRs and cytokines which is not yet clearly understood, and studies are ongoing to find the same.
Studies have reported that recreational drugs such as alcohol consumption (binge) and frequent or continuous use of amphetamines and methamphetamines induces psychosis-like symptoms in nearly half the users [78][79]. It was found that methamphetamine elevated IL-1β and IL-18 in primary mouse astrocyte cultures, and this was mediated by TLR4, NF-kB, and caspase-11 pathways, causing neuroinflammation [80]. This is the most probable reason why most of these users are at significant risk of schizophrenia where some of them develop psychosis, which eventually transforms into schizophrenia [81].

3.3. Genetics

Genetic polymorphisms represent DNA variation in a specific population that may/may not lead to a change in protein expression. One of the commonly occurring polymorphisms is a single nucleotide polymorphism (SNP), which has been used as a genetic target to study multiple diseases [82]. SNPs within multiple immune-related gene networks have now been investigated in terms of their association with disease risk. Among these, it was found that polymorphisms within genes encoding tlrs and their pathways were associated with either increased or decreased protection against various diseases and infections. Moreover, altered expression of cytokines in response to infections was associated with tlr gene polymorphisms [83].
In schizophrenia, gene polymorphisms associated with pathways of inflammation, immune response, neurodevelopment, and cell death have been identified. Alterations of such pathways due to polymorphisms are significantly associated with schizophrenia risk, and the TLR pathway is suggested to be a modulator of these pathways [84]. Studies also show that TLR polymorphisms are associated with schizophrenia (Table 3), such as tlr2 polymorphism in the Tunisian population [85]. An insertion/deletion polymorphism of an SNP (rs111200466) located in the promoter region of the tlr2 gene showed to be protective in healthy females, as this polymorphism was not observed in the schizophrenia group [85]. Missense polymorphisms (rs5743708 and rs121917864) located in the third exon of tlr2 gene were considered to increase the risk and susceptibility to schizophrenia. The aforementioned three SNPs were previously associated with decreased activation and expression of TLR2 and cytokines [85]. In another study, two SNPs, rs3804099 and rs3804100 (of unknown function), located in the third exon of tlr2 gene, were reported to be significantly associated with poor concentration in the Korean schizophrenia population. Although these 2 SNPs were found to be associated with cognition, none were associated with either positive or negative symptoms [86]. Patients belonging to north Indian ethnicity showed a similar association with tlr2 SNP (rs3804099) [87]. This indicates the broad (multiethnic) implications of TLR2 polymorphism in schizophrenia. TLR4 polymorphism also showed an association with schizophrenia risk; four SNPs of TLR4 were investigated, of which three (rs11536889-3′UTR, rs1927911-intron, and rs1927914-5′UTR) showed an association with schizophrenia. One of these investigated SNPs was previously associated with multiple diseases and disorders [88]. Changes in the TLR downstream signalling proteins such as myd88 SNP (rs7744-3′UTR) were reported to be less prominent in patients with schizophrenia than in controls. Moreover, a model utilising 5 SNPs (3 TLR downstream signalling protein genes (myd88, irak1, and nfkb1) and 2 cytokines (il6 and il1b)) for a five-way analysis identifies different combinations of these five genes, predicting the risk of schizophrenia in a given population. This model showed that people having a specific combination of these five genes were at higher risk (OR—6.9) of developing schizophrenia [9]. This evidence indicates the immune–genetic predisposition in schizophrenia, and it can be understood that multiple polymorphisms of various genes associated with the TLR pathway collectively contribute towards the incidence of schizophrenia (Table 3).
Table 3. Characteristics of genetic studies.
Study Population Gene (SNPs) Location of SNP Region of SNP SNP Function Analysis Results
Aflouk et al., 2021 [85] Tunisian tlr2 (rs111200466) Chr4. −196 to −174 Insertion/Deletion Promoter region Decreased activation and
expression of TLR2 and cytokines		 Protective action in females, as this
polymorphism was not observed in the schizophrenia group (females).
tlr2 (rs5743708) Chr4. G > A Missense variant Third exon (functional) Increases the risk and susceptibility to schizophrenia.
tlr2 (rs121917864) Chr4. C > T Missense variant
Kang et al., 2013 [86] Korean tlr2 (rs3804099) Chr4. T > C Synonymous Variant Third exon (functional) Unknown function C’ allele associated with
cognition (poor concentration).
tlr2 (rs3804100) Chr4. T > A/T > C Missense variant
Sharma et al., 2022 [87] Indian tlr2 (rs3804099) Chr4. T > C Synonymous Variant Third exon (functional) Unknown function Increases the risk of schizophrenia.
Mostafa et al., 2022 [88] Egyptian tlr4 (rs11536889) Chr9. G > A/G > C UTR Variant 3′UTR Interferes with the translation process and increase the expression of TLR4 A strong association between these
genes and schizophrenia.
tlr4 (rs1927911) Chr9. A > C/G/T Intron -
tlr4 (rs1927914) Chr9. G > A 5′UTR Regulation of gene expression and protein levels
García-Bueno et al., 2016 [9] Spanish myd88 (rs7744) Chr3. A > G/A > T Noncoding Transcript Variant 3′UTR Previously associated with autoimmune or inflammatory processes These two polymorphisms were found to be crucial in the schizophrenia predictive model for this population.
il6 (rs1800795) Chr7. C > G/C > T Promoter region Increases IL-6 levels
Characteristics of genetic studies illustrating polymorphisms in schizophrenia group in various populations. Chr—chromosome, A/G/T/C—nucleotide bases (adenine (A), cytosine (C), guanine (G), and thymine (T)), tlr—Toll-like receptor, il6—interleukin-6, myd88—myeloid differentiation primary response 88 protein, rsxxxxxx—reference SNP “ID”, SNP—single nucleotide polymorphism, rs—reference SNP, UTR—untranslated region.

This entry is adapted from the peer-reviewed paper 10.3390/biom13081188

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