LPAR2 (lysophosphatidic acid receptor 2)

Review on LPAR2 (lysophosphatidic acid receptor 2), with data on DNA, on the protein encoded, and where the gene is implicated

TLR2 and TLR4 as Potential Biomarkers of Environmental Particulate Matter Exposed Human Myeloid Dendritic Cells

In many subjects who are genetically susceptible to asthma, exposure to environmental stimuli may exacerbate their condition. However, it is unknown how the expression and function of a family of pattern-recognition receptors called toll-like receptors (TLR) are affected by exposure to particulate pollution. TLRs serve a critical function in alerting the immune system of tissue damage or infection—the so-called “danger signals”. We are interested in the role that TLRs play in directing appropriate responses by innate immunity, particularly dendritic cells (DC), after exposing them to particulate pollution. Dendritic cells serve a pivotal role in directing host immunity. Thus, we hypothesized that alterations in TLR expression could be further explored as potential biomarkers of effect related to DC exposure to particulate pollution. We show some preliminary data that indicates that inhaled particulate pollution acts directly on DC by down-regulating TLR expression and altering the activation state of DC. While further studies are warranted, we suggest that alterations in TLR2 and TLR4 expression should be explored as potential biomarkers of DC exposure to environmental particulate pollution

Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice

Oxidative stress has been postulated to play an important role in the pathogenesis of asthma; although a defect in antioxidant responses has been speculated to exacerbate asthma severity, this has been difficult to demonstrate with certainty. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor that is involved in the transcriptional regulation of many antioxidant genes. We show that disruption of the Nrf2 gene leads to severe allergen-driven airway inflammation and hyperresponsiveness in mice. Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates. Nrf2 disruption resulted in an increased expression of the T helper type 2 cytokines interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid and in splenocytes after allergen challenge. The enhanced severity of the asthmatic response from disruption of the Nrf2 pathway was a result of a lowered antioxidant status of the lungs caused by lower basal expression, as well as marked attenuation, of the transcriptional induction of multiple antioxidant genes. Our studies suggest that the responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to allergen-mediated asthma

A work group report on ultrafine particles (American Academy of Allergy, Asthma & Immunology): Why ambient ultrafine and engineered nanoparticles should receive special attention for possible adverse health outcomes in human subjects

Ultrafine particles (UFPs) are airborne particulates of less than 100 nm in aerodynamic diameter. Examples of UFPs are diesel exhaust particles, products of cooking, heating, and wood burning in indoor environments, and, more recently, products generated through the use of nanotechnology. Studies have shown that ambient UFPs have detrimental effects on both the cardiovascular and respiratory systems, including a higher incidence of atherosclerosis and exacerbation rate of asthma. UFPs have been found to alter and responses of the immune system to allergens and can also play a role in allergen sensitization. The inflammatory properties of UFPs can be mediated by a number of different mechanisms, including the ability to produce reactive oxygen species, leading to the generation of proinflammatory cytokines and airway inflammation. In addition, because of their small size, UFPs also have unique distribution characteristics in the respiratory tree and circulation and might be able to alter cellular function in ways that circumvent normal signaling pathways. Additionally, UFPs can penetrate intracellularly and potentially cause DNA damage. The recent advances in nanotechnology, although opening up new opportunities for the advancement of technology and medicine, could also lead to unforeseen adverse health effects in exposed human subjects. Further research is needed to clarify the safety of nanoscale particles, as well as the elucidation of the possible beneficial use of these particulates to treat disease

Activation of Epidermal Toll-Like Receptor 2 Enhances Tight Junction Function: Implications for Atopic Dermatitis and Skin Barrier Repair

Atopic dermatitis (AD) is characterized by epidermal tight junction (TJ) defects and a propensity for Staphylococcus aureus skin infections. S. aureus is sensed by many pattern recognition receptors, including Toll-like receptor 2 (TLR2). We hypothesized that an effective innate immune response will include skin barrier repair, and that this response is impaired in AD subjects. S. aureus–derived peptidoglycan (PGN) and synthetic TLR2 agonists enhanced TJ barrier and increased expression of TJ proteins, claudin-1 (CLDN1), claudin-23 (CLDN23), occludin, and Zonulae occludens 1 (ZO-1) in primary human keratinocytes. A TLR2 agonist enhanced skin barrier recovery in human epidermis wounded by tape stripping. Tlr2−/− mice had a delayed and incomplete barrier recovery following tape stripping. AD subjects had reduced epidermal TLR2 expression as compared with nonatopic subjects, which inversely correlated (r=-0.654, P=0.0004) with transepidermal water loss (TEWL). These observations indicate that TLR2 activation enhances skin barrier in murine and human skin and is an important part of a wound repair response. Reduced epidermal TLR2 expression observed in AD patients may have a role in their incompetent skin barrier

Respiratory syncytial virus infection influences tight junction integrity

Respiratory syncytial virus (RSV) is an important risk factor of asthma development and is responsible for severe respiratory tract infections. However, the influence of RSV infection on barrier function of bronchial epithelial cells in vitro and in vivo is still unclear. The aim of this study was to analyse the role of RSV in tight junction (TJ) regulation and to compare epithelial integrity between asthmatic and healthy individuals upon RSV infection. Healthy and asthmatic human bronchial epithelial cells (HBECs) were differentiated at air-liquid interface (ALI) and infected with RSV and ultraviolet (UV)-irradiated RSV. TJ expression and their integrity were analysed by quantitative polymerase chain reaction (qPCR), transepithelial resistance (TER) and paracellular flux. To determine the effect in vivo, BALB/c mice were infected intranasally with RSV or UV-irradiated RSV A2. Bronchoalveolar lavage and TJ integrity were analysed on days 1, 2, 4 and 6 post-infection by qPCR, bioplex and confocal microscopy. RSV increased barrier integrity in ALI cultures of HBEC from healthy subjects, but no effect was found in HBECs from asthmatics. This was not associated with an increase in TJ mRNA expression. In vivo, RSV induced lung inflammation in mice and down-regulated claudin-1 and occludin mRNA expression in whole lungs. Surprisingly, RSV infection was not observed in bronchial epithelial cells, but was found in the lung parenchyma. Decreased expression of occludin upon RSV infection was visible in mouse bronchial epithelial cells in confocal microscopy. However, there was no regulation of claudin-1 and claudin-7 at protein level

Characterization of STAT6 Target Genes in Human B Cells and Lung Epithelial Cells

Using ChIP Seq, we identified 556 and 467 putative STAT6 target sites in the Burkitt's lymphoma cell line Ramos and in the normal lung epithelial cell line BEAS2B, respectively. We also examined the positions and expression of transcriptional start sites (TSSs) in these cells using our TSS Seq method. We observed that 44 and 132 genes in Ramos and BEAS2B, respectively, had STAT6 binding sites in proximal regions of their previously reported TSSs that were up-regulated at the transcriptional level. In addition, 406 and 109 of the STAT6 target sites in Ramos and BEAS2B, respectively, were located in proximal regions of previously uncharacterized TSSs. The target genes identified in Ramos and BEAS2B cells in this study and in Th2 cells in previous studies rarely overlapped and differed in their identity. Interestingly, ChIP Seq analyses of histone modifications and RNA polymerase II revealed that chromatin formed an active structure in regions surrounding the STAT6 binding sites; this event also frequently occurred in different cell types, although neither STAT6 binding nor TSS induction was observed. The rough landscape of STAT6-responsive sites was found to be shaped by chromatin structure, but distinct cellular responses were mainly mediated by distinct sets of transcription factors

Mechanism of Sphingosine 1-Phosphate- and Lysophosphatidic Acid-Induced Up-Regulation of Adhesion Molecules and Eosinophil Chemoattractant in Nerve Cells

The lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) act via G-protein coupled receptors S1P1–5 and LPA1–3 respectively, and are implicated in allergy. Eosinophils accumulate at innervating cholinergic nerves in asthma and adhere to nerve cells via intercellular adhesion molecule-1 (ICAM-1). IMR-32 neuroblastoma cells were used as an in vitro cholinergic nerve cell model. The Gi coupled receptors S1P1, S1P3, LPA1, LPA2 and LPA3 were expressed on IMR-32 cells. Both S1P and LPA induced ERK phosphorylation and ERK- and Gi-dependent up-regulation of ICAM-1 expression, with differing time courses. LPA also induced ERK- and Gi-dependent up-regulation of the eosinophil chemoattractant, CCL-26. The eosinophil granule protein eosinophil peroxidase (EPO) induced ERK-dependent up-regulation of transcription of S1P1, LPA1, LPA2 and LPA3, providing the situation whereby eosinophil granule proteins may enhance S1P- and/or LPA- induced eosinophil accumulation at nerve cells in allergic conditions

Lung Megakaryocytes are Immune Modulatory Cells that Present Antigen to CD4+ T cells.

Although platelets are the cellular mediators of thrombosis, they are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered bone marrow–resident (BM-resident) cells. However, platelet-producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared with BM Mks. We therefore sought to define the immune functions of lung Mks. Using single-cell RNA sequencing of BM and lung myeloid-enriched cells, we found that lung Mks, which we term MkL, had gene expression patterns that are similar to antigen-presenting cells. This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment, as evidenced by BM Mks having an MkL-like phenotype under the influence of pathogen receptor challenge and lung-associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that MkL internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, MkL induced CD4+ T cell activation in an MHC II–dependent manner both in vitro and in vivo. These data indicated that MkL had key immune regulatory roles dictated in part by the tissue environment.pre-print236 K