TLR2, TLR3 and TLR5 regulation of pro-inflammatory and pro-labour mediators in human primary myometrial cells

Lim, Ratana; Barker, Gillian; Lappas, Martha

doi:10.1016/j.jri.2017.08.004

Cited by 29 publications

(22 citation statements)

References 51 publications

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“…Induction of Mincle by TLRs activates a cascade of events leading to the transcriptional regulation of proinflammatory genes . Our previous studies have shown that ligation of TLR‐2/6 ligand fsl‐1 and the TLR‐3 ligand poly(I:C) can induce pro‐labour mediators in human myometrial and amnion cells . Thus, it was of interest to determine if Mincle is also involved in TLR signalling.…”

Section: Discussionmentioning

confidence: 99%

“…There are four main classes of PPRs; Toll‐like receptors (TLRs), NOD‐like receptors (NLRs), RIG‐I‐like receptors (RLRs) and C‐type lectin receptors (CLRs). TLRs and NLRs have been shown to play a role in regulating the inflammatory processes associated with human labour . There are, however, no studies on the expression and function of CLRs in parturition.…”

Section: Introductionmentioning

confidence: 99%

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Expression and function of macrophage-inducible C-type lectin (Mincle) in inflammation driven parturition in fetal membranes and myometrium

Lim

Lappas

2019

Clinical and Experimental Immunology

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The pivotal role of inflammatory processes in human parturition is well known, but not completely understood. We have performed a study to examine the role of macrophage-inducible C-type lectin (Mincle) in inflammation-associated parturition. Using human samples, we show that spontaneous labour is associated with up-regulated Mincle expression in the myometrium and fetal membranes. Mincle expression was also increased in fetal membranes and myometrium in the presence of pro-labour mediators, the proinflammatory cytokines interleukin (IL)-1B and tumour necrosis factor (TNF), and Toll-like receptor (TLR) ligands fsl-1, poly(I:C), lipopolysaccharide (LPS) and flagellin. These clinical studies are supported by mouse studies, where an inflammatory challenge in a mouse model of preterm birth increased Mincle expression in the uterus. Importantly, elimination of Mincle decreased the effectiveness of proinflammatory cytokines and TLR ligands to induce the expression of pro-labour mediators; namely, proinflammatory cytokines and chemokines, contraction-associated proteins and prostaglandins, and extracellular matrix remodelling enzymes, matrix metalloproteinases. The data presented in this study suggest that Mincle is required when inflammatory activation precipitates parturition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression and function of macrophage-inducible C-type lectin (Mincle) in inflammation driven parturition in fetal membranes and myometrium

Lim

Lappas

2019

Clinical and Experimental Immunology

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“…This observation is not surprising in view of the range of known non-immune functions of toll-like receptors (Anthoney et al, 2018). In the particular case of calving ease, the effect of TLR4 variation might reflect a role in the inflammatory response and myometrial signalling before parturition, which is mediated by the MyD88/TRAF6/NF-κB pathway (Lim et al, 2017). The intronic localization of the SNP 5087A > G together with its multi-faceted effects points again to the importance of linkage in the haplotype structure for the detection of phenotypic associations.…”

Section: Tlr4 Polymorphismmentioning

confidence: 94%

Potential of <i>TLR</i>-gene diversity in Czech indigenous cattle for resistance breeding as revealed by hybrid sequencing

et al. 2019

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Abstract. A production herd of Czech Simmental cattle (Czech Red Pied, CRP), the conserved subpopulation of this breed, and the ancient local breed Czech Red cattle (CR) were screened for diversity in the antibacterial toll-like receptors (TLRs), which are members of the innate immune system. Polymerase chain reaction (PCR) amplicons of TLR1, TLR2, TLR4, TLR5, and TLR6 from pooled DNA samples were sequenced with PacBio technology, with 3–5× coverage per gene per animal. To increase the reliability of variant detection, the gDNA pools were sequenced in parallel with the Illumina X-ten platform at low coverage (60× per gene). The diversity in conserved CRP and CR was similar to the diversity in conserved and modern CRP, representing 76.4 % and 70.9 % of its variants, respectively. Sixty-eight (54.4 %) polymorphisms in the five TLR genes were shared by the two breeds, whereas 38 (30.4 %) were specific to the production herd of CRP; 4 (3.2 %) were specific to the broad CRP population; 7 (5.6 %) were present in both conserved populations; 5 (4.0 %) were present solely for the conserved CRP; and 3 (2.4 %) were restricted to CR. Consequently, gene pool erosion related to intensive breeding did not occur in Czech Simmental cattle. Similarly, no considerable consequences were found from known bottlenecks in the history of Czech Red cattle. On the other hand, the distinctness of the conserved populations and their potential for resistance breeding were only moderate. This relationship might be transferable to other non-abundant historical cattle breeds that are conserved as genetic resources. The estimates of polymorphism impact using Variant Effect Predictor and SIFT software tools allowed for the identification of candidate single-nucleotide polymorphisms (SNPs) for association studies related to infection resistance and targeted breeding. Knowledge of TLR-gene diversity present in Czech Simmental populations may aid in the potential transfer of variant characteristics from other breeds.

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“…The inflammatory response begins with bacteria or stressed cells that induce release of small motives (Pathogen/Danger-Associated Molecular Patterns) that are recognized by Toll-like receptors (TLR; receptors part of the innate immune system) expressed throughout gestational tissues. This leads to the production of pro-inflammatory cytokines and chemokines [33], extravasation of myeloid and lymphoid inflammatory cells (mostly neutrophils and monocytes/macrophages), and eventually, activation of many uterine activation proteins (UAPs). These UAPs promote cervical ripening, fetal membrane weakening, contractions and labor [34][35][36].…”

Section: Inflammation In Preterm Birthmentioning

confidence: 99%

Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

Mai-Vo¹,

Nadeau-Vallée²,

Beaudry-Richard³

2017

UOJM

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Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity. Although the severity of neonatal outcomes is inversely correlated with gestational age, all PTBs can lead to potentially life-threatening neonatal outcomes and major lifelong health complications. Because advances in neonatal care have substantially decreased neonatal mortality, the incidence of PTB and its complications is unabatedly rising. PTB currently affects more than 10% of births worldwide, with similar numbers in developed countries. Correspondingly, improving neonatal outcome is a key objective of the World Health Organization. The recently approved (in Europe) tocolytics drug, Atosiban, used to prolong preterm gestation, has not been shown to improve neonatal outcome, nor have other tocolytic agents used in clinic. Thus, PTB remains an unmet medical need. Recent evidence shows that most, if not all, PTBs are associated with (overt or occult) inflammatory processes in gestational tissues, independent of infection. Proinflammatory cytokines are produced from maternal and fetal cells in response to sterile or infectious stressors. These seem to orchestrate a multi-tissue response including myometrial contractility, cervical ripening, and weakening/rupture of fetal membranes, leading to the onset of preterm labor. This integrated system might have been conserved through mammalian evolution due to increased maternal and/or fetal survival when gestation is terminated in specific settings, such as infection. Hence, inflammation may be a common pathway to the numerous aetiologies of PTB. Most importantly, recent evidence suggests that inflammation is transmitted to the fetus, thereby inducing organ injuries that may underlie the development of major neonatal diseases. Targeting inflammation prenatally instead of myometrial contraction could be a more successful and safe approach for the management of PTB, as suggested by recent animal studies. ABSTRACTLa naissance prématurée est la principale cause de mortalité et de morbidité néonatale. Bien que la sévérité des issus néonataux soit inversement corrélée avec l'âge gestationnel à la naissance, toutes les naissances prématurées peuvent mener à des issus néonataux potentiellement mortels et à des complications avec répercussions s'échelonnant sur toute la vie. Étant donné que la mortalité néonatale a considérablement diminuée avec les récentes avancées en néonatalogie, l'incidence de la naissance préma-turée et de ses complications sont en hausse. La naissance prématurée affecte présentement plus de 10% des naissances à travers le monde, avec des taux similaires dans les pays développés. Conséquemment, d'améliorer l'issu néonatal est un objectif clé de l'Organisation Mondiale de la Santé. Le tocolytique Atosiban récemment approuvé (en Europe) pour prolonger les gestations pré-maturées n'a pas démontré d'efficacité pour améliorer les issus néonataux, tout comme les autres tocolytiques utilisés en clinique, et la naissance prématurée demeure un besoin médical non-atteint. Des données r...

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TLR2, TLR3 and TLR5 regulation of pro-inflammatory and pro-labour mediators in human primary myometrial cells

Cited by 29 publications

References 51 publications

Expression and function of macrophage-inducible C-type lectin (Mincle) in inflammation driven parturition in fetal membranes and myometrium

Expression and function of macrophage-inducible C-type lectin (Mincle) in inflammation driven parturition in fetal membranes and myometrium

Potential of <i>TLR</i>-gene diversity in Czech indigenous cattle for resistance breeding as revealed by hybrid sequencing

Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

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TLR2, TLR3 and TLR5 regulation of pro-inflammatory and pro-labour mediators in human primary myometrial cells

Cited by 29 publications

References 51 publications

Expression and function of macrophage-inducible C-type lectin (Mincle) in inflammation driven parturition in fetal membranes and myometrium

Expression and function of macrophage-inducible C-type lectin (Mincle) in inflammation driven parturition in fetal membranes and myometrium

Potential of &lt;i&gt;TLR&lt;/i&gt;-gene diversity in Czech indigenous cattle for resistance breeding as revealed by hybrid sequencing

Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

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Potential of <i>TLR</i>-gene diversity in Czech indigenous cattle for resistance breeding as revealed by hybrid sequencing