Epigenetic Regulation of Tolerance to Toll-Like Receptor Ligands in Alveolar Epithelial Cells

Neagos, Jacqueline; Standiford, Theodore J.; Newstead, Michael W.; Zeng, Xianying; Huang, Steven K.; Ballinger, Megan N.

doi:10.1165/rcmb.2015-0057oc

Cited by 28 publications

(27 citation statements)

References 55 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We hypothesized TLR2 stimulation may induce regulatory histone modifications at tight junction complex gene loci. [43][44][45] We performed chromatin immunoprecipitation (ChIP) assays of EPC2-hTERT cells following stimulation with zymosan ( Figure 6) to assess for changes in the chromatin environment at the promoter and enhancer of CLDN1 and TJP1. Acetylation of histone H4 was significantly increased at the CLDN1 enhancer and promoter and decreased in the TJP1 promoter of zymosan-treated samples.…”

Section: Histone Modifications In Zymosan-treated Epithelial Cellsmentioning

confidence: 99%

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

Ruffner

Song

Maurer

et al. 2019

Allergy

View full text Add to dashboard Cite

Background: Germline-encoded innate immune pattern recognition receptors (PRR) are expressed at epithelial surfaces and modulate epithelial defenses. Evidence suggests that stimulation of the Toll-like receptor (TLR) family of PRR may regulate epithelial barrier integrity by upregulating tight junction (TJ) complex protein expression, but it is not known whether this mechanism is utilized in esophageal epithelial cells.TJ complex proteins maintain intact barrier function and are dysregulated in atopic disorders including eosinophilic esophagitis. Methods: Pattern recognition receptors expression was assessed in EoE and controlprimary esophageal epithelial cells, demonstrating robust expression of TLR2 and TLR3. The three-dimensional air-liquid interface culture (ALI) model was used to test whether TLR2 or TLR3 stimulation alters epithelial barrier function using an in vitro model of human epithelium. Transepithelial electrical resistance (TEER) and FITC-Dextran permeability were evaluated to assess membrane permeability. ALI cultures were evaluated by histology, immunohistochemistry, Western blotting, and chromatin immunoprecipitation (ChIP).Results: TLR3 stimulation did not change TEER in the ALI model. TLR2 stimulation increased TEER (1.28-to 1.31-fold) and decreased paracellular permeability to FITC-Dextran, and this effect was abolished by treatment with anti-TLR2 blocking antibody. TJ complex proteins claudin-1 and zonula occludens-1 were upregulated following TLR2 stimulation, and ChIP assay demonstrated altered histone 4 acetyl binding at the TJP1 enhancer and CLDN1 enhancer and promoter following zymosan treatment, implying the occurrence of durable chromatin changes. Conclusions:Our findings implicate the TLR2 pathway as a potential regulator of esophageal epithelial barrier function and suggest that downstream chromatin modifications are associated with this effect. K E Y W O R D Seosinophilic esophagitis, epithelium, innate immunity, tight junctions, toll-like receptors

show abstract

Section: Histone Modifications In Zymosan-treated Epithelial Cellsmentioning

confidence: 99%

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

Ruffner

Song

Maurer

et al. 2019

Allergy

View full text Add to dashboard Cite

show abstract

“…The study examined the effects of TLR stimulation on chemokine production in alveolar epithelial cells (AECs), it was found that upon repeated stimulation of AECs with TLR ligands it was noted a 'tolerance' response developed, but that addition of HDAC inhibitors circumvented this response. 111 Similarly, another study showed that activation of TLR4 with LPS resulted in the repression of certain HDACs as well as the increase in expression of others. The study noted that LPS seemed to regulate the expression of several HDACs at the mRNA level in mouse-derived macrophages.…”

Section: Hdacs Inhibitors and Immunitymentioning

confidence: 96%

“…A 2015 study has shown that histone acetylation may play a role in the development of tolerance to pathogens in the lungs. The study examined the effects of TLR stimulation on chemokine production in alveolar epithelial cells (AECs), it was found that upon repeated stimulation of AECs with TLR ligands it was noted a ‘tolerance’ response developed, but that addition of HDAC inhibitors circumvented this response 111 …”

Section: Hdacs Inhibitors and Immunitymentioning

confidence: 99%

Epigenetics and innate immunity: the ‘unTolld’ story

Hennessy

McKernan

2016

Immunol Cell Biol

View full text Add to dashboard Cite

Toll-like receptors (TLRs) are a family of 13 receptors known as pattern-recognition receptors (PRRs) and have a key role in the innate immune response. The TLRs are activated by pathogen-associated molecular patterns (PAMPs) that are structurally conserved molecules present on the surfaces of bacteria and viruses. The activation of these TLRs by pathogens results in the downstream activation of genes involved in the production of proinflammatory factors. There is a lack of understanding on the mechanisms by which TLR gene expression is regulated. Epigenetics could be one such mechanism, which is concerned with changes in gene expression/products that arise without a change in the nucleotide sequence. These changes are brought about by two main mechanisms, DNA methylation and histone modifications. This review seeks to examine the current knowledge regarding the epigenetic regulation of this family of receptors and their signalling pathways.

show abstract

“…(1) PRRs: Because the cost of tissue damage is high and may result in the permanent loss of physiological function, repair mechanisms must be initiated from the onset of the infection. Interestingly, the overall effects of single nucleotide polymorphisms in genes encoding TLRs or their signaling components appear to have only a modest effect on host resistance to infectious diseases, thus suggesting a potentially important role in host tolerance (Neagos et al 2015). Matzinger (2002) initially suggested that the activation of TLRs via DAMPs would serve as an early Balarm signal^of tissue damage for the initiation of the repair process.…”

Section: Host Tolerance In Acute Pulmonary Infectionmentioning

confidence: 99%

Unravelling the networks dictating host resistance versus tolerance during pulmonary infections

et al. 2017

View full text Add to dashboard Cite

The appearance of single cell microorganisms on earth dates back to more than 3.5 billion years ago, ultimately leading to the development of multicellular organisms approximately 3 billion years later. The evolutionary burst of species diversity and the "struggle for existence", as proposed by Darwin, generated a complex host defense system. Host survival during infection in vital organs, such as the lung, requires a delicate balance between host defense, which is essential for the detection and elimination of pathogens and host tolerance, which is critical for minimizing collateral tissue damage. Whereas the cellular and molecular mechanisms of host defense against many invading pathogens have been extensively studied, our understanding of host tolerance as a key mechanism in maintaining host fitness is extremely limited. This may also explain why current therapeutic and preventive approaches targeting only host defense mechanisms have failed to provide full protection against severe infectious diseases, including pulmonary influenza virus and Mycobacterium tuberculosis infections. In this review, we aim to outline various host strategies of resistance and tolerance for effective protection against acute or chronic pulmonary infections.

show abstract

Epigenetic Regulation of Tolerance to Toll-Like Receptor Ligands in Alveolar Epithelial Cells

Cited by 28 publications

References 55 publications

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

Epigenetics and innate immunity: the ‘unTolld’ story

Unravelling the networks dictating host resistance versus tolerance during pulmonary infections

Contact Info

Product

Resources

About