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TLR Activation/Dysregulation leads to Increased proinflammatory mediators
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding of SARS-CoV-2 to ACE2 receptor leading to acute respiratory distress associated mortality||adjacent||High||Not Specified||Young Jun Kim (send email)||Open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
The engagement of TLR with Pathogen-Associated Molecular Patterns (PAMPs) and host derived damage-associated molecular patterns (DAMPs) induces conformational changes of TLRs that allow recruitment of adaptor proteins such as MyD88, TIRAP, TRIF, and TRAM to control intracellular signaling pathways, including ERK, p38 and NF-B, driving the synthesis and secretion of cytokines and chemokines [Kawai, T.; Akira, S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol. Med. 2007, 13, 460–469] [DOI:https://doi.org/10.1016/j.molmed.2007.09.002]. In a healthy state the amount and type of proinflammatory mediators are appropriate to required circumstances (e.g. defence against invading pathogens) and resolution of inflammation is promoted to reestablish homeostasis. Dysregulated TLR Activation can result from e.g. overabundance of PAMPS/DAMPS or over-, or under-expression of TLR protein intra- and/or extracellularly or over- or under-expression of downstream proteins. These circumstances can be modulated by a number of factors including biological/intrinsic factors (e.g. age, sex, genetic factors), pre-existing co-morbidities, lifestyle factors, environmental factors and therapeutic interventions. In context of an adverse outcome the resulting dysregulated over- or under-activation of TLRs contributes to dysproportional amounts of proinflammatory mediators (overproduction or underproduction) halting back defence and homeostasis.
Evidence Collection Strategy
Evidence Supporting this KER
Evidence in support of this KER in context of COVID-19:
Uncertainties and Inconsistencies
Known modulating factors
|Modulating Factor (MF)||MF Specification||Effect(s) on the KER||Reference(s)|
PFOA exposure reduces TLR2 and Myd88 expression in zebrafish and induces a dose-dependent increase in IFN and B-cell-activating factor (BAFF) mRNA levels .
The TLR/MyD88/NF-kB pathway could be a mechanism through which PFOA interferes with BAFF and IFN expression .
Increasing TLR2 expression in zebrafish exposed to PFOA showed a linear correlation with increased levels of MyD88, IL-1β, and IL-21 mRNA levels .
2) doi: 10.1186/2045-7022-3-S3-O5
3) doi: 10.1016/j.jhazmat.2014.08.043
|SEX||male sex (XY chromosome)||
Male and female subjects both express functionally active TLRs, but sex differences have been reported. TLR3, TLR4 and TLR7 are coded by the X chromosome. Thus, certain TLR gain and/or loss of function polymorphisms have higher clinical prevalence in men. Particularly, TLR7 localizes to an area of the X chromosome known to escape X-chromosome inactivation . TLR7 is more highly expressed at the protein level by female immune cells than by male ones . A study showed that specific TLR7 loss of function variants lead to poor outcome of SARS-CoV-2, which could be explained via the role of TLR7 in responding to SARS-CoV-2 mRNA recognition by inducing the production of the antiviral cytokine interferon-a (IFN-a) . An X-linked recessive TLR7 deficiency was found present in approximately 1% of men under 60 years old with life-threatening COVID-19) . Plasmacytoid dendritic cells of men with these TLR7 variants produce less IFN-a ex vivo, which could explain their poor defence against SARS-CoV-2 . Sex-specific associations between TLR polymorphisms and poor lung function have been reported . Examples include gain of function polymorphisms of rs187084 in the TLR9 gene displaying significantly lower lung function in male swine operators than those with wild type. Additionally, the gain of function polymorphisms TLR9-1237T/C, rs5743836 is a risk for severe sepsis in pediatric critical care patients, with males having a higher risk and a more pronounced allele frequency of TLR9-1237T/C than females . The sex hormone, testosterone, can reduce TLR4 expression and sensitivity, which is proposed to explain in part the less optimal defence during infection in male compared to female .
1) doi: 10.1126/sciimmunol.aap8855
2) doi: 10.1126/sciimmunol.abl4348
3) doi: 10.1080/15287394.2018.1544523
4) Elsherif et al., Int J Clin Exp Med 2019;12(4):4381-4386
|Age||Young/old people||In older people, there are studies indicating both an increase and decrease in TLR expression and signalling [1,2,3]. Renshaw et al.  showed a decline in TLR expression and function in aged mice, explanatory for increased susceptibility to infections and poor adaptive immune responses in aging. On the other hand, Olivieri et al.  reported that the effect of age on signalling events downstream of TLRs is greater than the effect of age on TLR levels. They suggested that inflammaging can be triggered by an impairment of miRNAs/TLR signalling interaction (in endothelial and immune system cells), leading to activation of immune cells over time. Inflammaging is a higher basal inflammatory state in older subjects, which is a major driving force of frailty and common severe age-related diseases. Other complex age-dependent TLRs signalling mechanism include the decreased ability of aged macrophages to fight pathogens, the accumulation of senescent cells in aged subjects, and the increased release of endogenous TLRs ligands from senescence cells.||
Obesity influences TLR9 expression, which is higher in visceral compared to subcutaneous adipose tissue depots in mice and obese patients . Obesity induced cell-free DNA fragments released from adipocytes stimulate chronic adipose tissue inflammation and insulin resistance via TLR9 activation 
2. doi: 10.1126/sciadv.1501332
|Vitamin D (moderate evidence)||Vitamin D deficiency||
Vitamin D status modulates cytokine production, at least partly through the differential modulation of TLRs. Vitamin D3 down-regulates TLR9 in human monocytes but not TLR3, which resulted in less secretion of IL-6 in response to TLR9 challenge . High-dose oral supplementation of vitamin D3 (4000 IU/day) in human decreased TLR9 protein levels and mRNA expression of TLR3, TLR7, and TLR9 .
 doi: 10.1007/s11010-019-03658-w
It is well-documented that the TLR expression is determined by genetic variation within the TLR genes . In addition to the already mentioned sex differences in certain TLR polymorphisms, TLR genes also exhibit a distinct population distribution pattern and are the target of selection pressure. Ethnicity disparity in COVID-19 mortality rates were suggested to be explained in part by elevated gene expression of TLR7 and TLR9. In addition, allelic variation in the TLR adaptor protein, Ticam2, influences susceptibility to SARS-CoV infection in mice as Ticam2-/- mice had high susceptibility to SARS-CoV-2 infection .
 doi: 10.1096/fj.202001115R
 doi: 10.1016/j.clim.2020.108481
|Pre-existing heart failure||
TLRs are expressed in the myocardium, with TLR4 being the most abundantly expressed, and TLR2 and TLR3 being present to a lesser extent .
TLR4 is upregulated in failing hearts [2-4]. The higher expression of TLR4 in HF patients could predispose them towards pro-inflammatory responses. Evidence shows that the S proteins of SARS-CoV-2 can bind to TLR4 directly or activate it via DAMP- and PAMP-mediated pathways, and thus, induce pro-inflammatory mediators, such as IL-1, IL-6 and TNF-α .
The mediator of this TLR-induced activation appears to be NF-κB , an essential transcription factor involved in various cardiovascular pathologies .
In addition, following infection by SARS-CoV-2 of adult rat cardiac tissue resident macrophage-derived fibrocytes, TLR4 was further activated with a dual effect: it caused the upregulation of ACE2 and induced a pro-inflammatory M1 polarization of macrophages , which can further enhance the pro-inflammatory factors secretion. However, the involvement of pre-existing HF in the modulation of COVID-19 via TLRs is still not fully elucidated but deserves further investigation.
|Diet||High-fat diets impact TLR-mediated inflammation||