Lamkioued and Gounni discuss the study by Moon and colleagues which enhance the understanding of the role and specific mechanisms by which tissue-resident macrophages resolve eosinophil allergic lung ...inflammation. Asthma is a heterogeneous chronic respiratory disease triggered by epithelial barrier integrity disruption due to environmental insults such as airborne allergens. In type 2-high asthma, injured airway epithelial cells secrete innate immune cytokines that promote the stimulation of T-helper 2 cells and type 2 innate lymphoid cells and recruit other immune cells, such as eosinophils. It is widely believed that high pulmonary eosinophil counts and actions of preformed toxic proteins released by activated eosinophils are associated with asthma symptoms and severity.
Previous studies have shown that delayed neutrophil apoptosis is associated with chronic airway diseases. Leptin is an adipocyte-derived hormone that acts as a regulator of energy homeostasis and ...food intake. Emerging evidence suggests that leptin can regulate immune responses including the release of proinflammatory cytokines and protection of inflammatory cells from apoptosis. Serum leptin is increased during allergic reactions in the airways. However, the expression and function of leptin receptor in neutrophils isolated from children is not known.
Flow cytometry was used to detect leptin receptor expression in neutrophils isolated from allergic asthmatic (n = 14), allergic non asthmatic (n = 21), non allergic asthmatic (n = 7) and healthy children (n = 23); confocal laser scanning microscopy combined with immunofluorescence was performed to detect intracellular pool of leptin receptor; Annexin-V/PI staining and caspase 3 activity was used to determine neutrophil survival. Pharmacological inhibitors were utilized to understand the role of MAPK and NF-κB pathway in leptin-induced neutrophil survival.
A heterogeneous leptin receptor expression was observed on neutrophils isolated from children. Neutrophils isolated from healthy children expressed more leptin receptor than those from allergic asthmatic (P<0.05) but not allergic non-asthmatic (P>0.05) or non-allergic asthmatic children (n = 7, P>0.05). Neutrophils isolated from children express an intracellular pool of leptin receptor that was mobilized to the cell surface upon GM-CSF stimulation. Finally, leptin exhibited anti-apoptotic properties on neutrophils via NF-κB and MEK1/2 MAPK pathway. Collectively, our data suggest that leptin may enhance airway inflammation by promoting neutrophil survival.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gounni and Koussih discuss the study of Liang et al in which they demonstrate that SUMOylation plays a critical role in the expression of long isoform thymic stromal lymphopoietin (lfTSLP) in airway ...epithelial cells. They show enhanced SUMOylation in the airway epithelium using a chronic house dust mite (HDM) mouse model of allergic asthma. Treatment with the SUMOylation inhibitor 2-D08 downregulates BAL eosinophil and neutrophil concentrations, mucus cell hyperplasia, serum HDM-specific IgE, and airway hyperreactivity. In conclusion, the study highlights the role of post-translational modification on the expression and functional activity of lfTSLP protein, which may pave the way for specific strategies targeting lfTSLP without affecting sfTSLP (short isoform TSLP), considered to have antidefense properties.
Neutrophil-dominated inflammation plays an important role in many airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiolitis and cystic fibrosis. In cases of asthma ...where neutrophil-dominated inflammation is a major contributing factor to the disease, treatment with corticosteroids can be problematic as corticosteroids have been shown to promote neutrophil survival which, in turn, accentuates neutrophilic inflammation. In light of such cases, novel targeted medications must be developed that could control neutrophilic inflammation while still maintaining their antibacterial/anti-fungal properties, thus allowing individuals to maintain effective innate immune responses to invading pathogens. The aim of this review is to describe the molecular mechanisms of neutrophil apoptosis and how these pathways are modulated by glucocorticoids. These new findings are of potential clinical value and provide further insight into treatment of neutrophilic inflammation in lung disease.
Background Thymic stromal lymphopoietin (TSLP) plays a pivotal role in the initiation of allergic airway inflammation. This cytokine is produced by several cell types, including human epithelial ...cells. Objective We sought to determine the effect of TSLP on proliferation and repair of epithelial cells isolated from asthmatic patients and healthy subjects. Methods Expression of TSLP receptor (TSLPR) and its response to inhaled corticosteroids was evaluated on bronchial biopsy specimens of healthy control subjects and asthmatic patients by means of immunohistochemistry. TSLPR, TSLP, and IL-13 mRNA expression was determined by means of quantitative PCR, and protein expression was measured by means of ELISA and Western blotting in epithelial cells isolated from asthmatic subjects compared with those isolated from healthy control subjects. The effect of TSLP on cell proliferation and wound healing was performed. Results TSLPR is expressed by bronchial epithelial cells in bronchial biopsy specimens and in cultured cells, with no difference between asthmatic patients and healthy control subjects. Inhaled corticosteroids did not affect this expression. TSLP mRNA and protein levels were significantly higher in epithelial cells isolated from asthmatic patients compared with those from healthy control subjects. TSLP stimulated IL-13 production by bronchial epithelial cells. TSLP induced airway epithelial cell proliferation and enhanced epithelial injury repair. This effect was abrogated with IL-13 neutralization. Conclusions Our data indicate that epithelial cells express TSLPR and that TSLP induces bronchial epithelial cell proliferation and increases injury repair through IL-13 production. This suggests that TSLP and IL-13 loops play a homeostatic role on epithelial cell proliferation and repair.
Asthma is a heterogenous airway disease characterized by airway inflammation and remodeling. It affects more than 300 million people worldwide and poses a significant burden on society. Semaphorins, ...discovered initially as neural guidance molecules, are ubiquitously expressed in various organs and regulate multiple signaling pathways. Interestingly, Semaphorin3E is a critical molecule in lung pathophysiology through its role in both lung development and homeostasis. Semaphorin3E binds to plexinD1, mediating regulatory effects on cell migration, proliferation, and angiogenesis. Recent in vitro and in vivo studies have demonstrated that the Semaphorin3E-plexinD1 axis is implicated in asthma, impacting inflammatory and structural cells associated with airway inflammation, tissue remodeling, and airway hyperresponsiveness. This review details the Semaphorin3E-plexinD1 axis in various aspects of asthma and highlights future directions in research including its potential role as a therapeutic target in airway allergic diseases.
Regulation of dendritic cell functions is a complex process in which several mediators play diverse roles as a network in a context-dependent manner. The precise mechanisms underlying dendritic cell ...functions have remained to be addressed. Semaphorins play crucial roles in regulation of various cell functions. We previously revealed that Semaphorin 3E (Sema3E) contributes to regulation of allergen-induced airway pathology partly mediated by controlling recruitment of conventional dendritic cell subsets in vivo, though the underlying mechanism remained elusive. In this study, we investigate the potential regulatory role of Sema3E in dendritic cells. We demonstrated that bone marrow-derived dendritic cells differentiated from Sema3e.sup.-/- progenitors have an enhanced migration capacity both at the baseline and in response to CCL21. The enhanced migration ability of Sema3E dendritic cells was associated with an overexpression of the chemokine receptor (CCR7), elevated Rac1 GTPase activity and F-actin polymerization. Using a mouse model of allergic airway sensitization, we observed that genetic deletion of Sema3E leads to a time dependent upregulation of CCR7 on CD11b.sup.+ conventional dendritic cells in the lungs and mediastinal lymph nodes. Furthermore, aeroallergen sensitization of Sema3e.sup.-/- mice lead to an enhanced expression of PD-L2 and IRF-4 as well as enhanced allergen uptake in pulmonary CD11b.sup.+ DC, compared to wild type littermates. Collectively, these data suggest that Sema3E implicates in regulation of dendritic cell functions which could be considered a basis for novel immunotherapeutic strategies for the diseases associated with defective dendritic cells in the future.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Spinal cord injury (SCI) triggers a robust neuroinflammatory response that governs secondary injury mechanisms with both degenerative and pro-regenerative effects. Identifying new immunomodulatory ...therapies to promote the supportive aspect of immune response is critically needed for the treatment of SCI. We previously demonstrated that SCI results in acute and permanent depletion of the neuronally derived Neuregulin-1 (Nrg-1) in the spinal cord. Increasing the dysregulated level of Nrg-1 through acute intrathecal Nrg-1 treatment enhanced endogenous cell replacement and promoted white matter preservation and functional recovery in rat SCI. Moreover, we identified a neuroprotective role for Nrg-1 in moderating the activity of resident astrocytes and microglia following injury. To date, the impact of Nrg-1 on immune response in SCI has not yet been investigated. In this study, we elucidated the effect of systemic Nrg-1 therapy on the recruitment and function of macrophages, T cells, and B cells, three major leukocyte populations involved in neuroinflammatory processes following SCI.
We utilized a clinically relevant model of moderately severe compressive SCI in female Sprague-Dawley rats. Nrg-1 (2 μg/day) or saline was delivered subcutaneously through osmotic mini-pumps starting 30 min after SCI. We conducted flow cytometry, quantitative real-time PCR, and immunohistochemistry at acute, subacute, and chronic stages of SCI to investigate the effects of Nrg-1 treatment on systemic and spinal cord immune response as well as cytokine, chemokine, and antibody production.
We provide novel evidence that Nrg-1 promotes a pro-regenerative immune response after SCI. Bioavailability of Nrg-1 stimulated a regulatory phenotype in T and B cells and augmented the population of M2 macrophages in the spinal cord and blood during the acute and chronic stages of SCI. Importantly, Nrg-1 fostered a more balanced microenvironment in the injured spinal cord by attenuating antibody deposition and expression of pro-inflammatory cytokines and chemokines while upregulating pro-regenerative mediators.
We provide the first evidence of a significant regulatory role for Nrg-1 in neuroinflammation after SCI. Importantly, the present study establishes the promise of systemic Nrg-1 treatment as a candidate immunotherapy for traumatic SCI and other CNS neuroinflammatory conditions.
Background Chronic airway diseases, including asthma, are characterized by increased airway smooth muscle (ASM) mass that is due in part to growth factor-mediated ASM cell proliferation and ...migration. However, the molecular mechanisms underlying these effects are not completely understood. Semaphorin 3E (Sema3E) has emerged as an essential mediator involved in cell migration, proliferation, and angiogenesis, although its role in ASM cell function is not investigated. Objectives We sought to determine the expression of Sema3E receptor, plexinD1, in human ASM cells (HASMCs); effect of Sema3E on basal and platelet-derived growth factor (PDGF)-induced proliferation and migration; and underlying signaling pathways. Methods Expression of plexinD1 in HASMCs was studied with RT-PCR, immunostaining, and flow cytometry. The effect of Sema3E on HASMC proliferation and migration was evaluated by 5-ethynyl-2′-deoxyuridine (EdU) incorporation, cell count, and Boyden chamber assay. Sema3E-mediated intracellular signaling was investigated with fluorescent microscopy, flow cytometry, Rac1 activation, and Western blot analysis. Results HASMCs from healthy persons expressed plexinD1 more than HASMCs from asthmatic patients. Sema3E increased plexinD1 expression in HASMCs from asthmatic patients. Recombinant Sema3E inhibited PDGF-mediated HASMC proliferation and migration, which was associated with F-actin depolymerization, suppression of PDGF-induced Rac1 guanosine triphosphatase activity, and Akt and extracellular signal-regulated kinase 1 and 2 phosphorylation. Bronchial biopsies from patients with mild asthma displayed immunoreactivity of plexinD1, suggesting the potential in vivo role of Sema3E–PlexinD1 axis in HASMC function. Conclusion This study provides the first evidence that Sema3E receptor is expressed and plays functional roles in HASMCs. Our data suggest a regulatory role of Sema3E in PDGF-mediated proliferation and migration, leading to downregulation of ASM remodeling.
Pentraxin-3 (PTX3) is a multifunctional protein involved in both innate and adaptive immunity. Glucocorticoid (GC) is the first-line therapy to mitigate airway inflammation in asthma. Previous pieces ...of evidence showed that GC has divergent effects on PTX3 production in various cell types. The molecular mechanisms controlling PTX3 expression in HASMC are, however, not yet characterized. In this study, we demonstrate that the synthetic GC, dexamethasone (DEX) increases the expression of PTX3 both at the protein and mRNA levels. We also found that such an effect of DEX was dependent on de novo protein synthesis and the GC receptor (GR). While DEX increases PTX3 mRNA stability, it did not affect its promoter activity. Interestingly, HASMC pre-treated with p42/p44 ERK inhibitor, but not with p38 or JNK-MAPK inhibitors, significantly interfered with DEX-induced PTX3 secretion. Taken together, our data suggest that GC regulates PTX3 expression in HASMC through transcriptional and post-transcriptional mechanisms in a GR and ERK-dependent manner.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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