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1.
Nat Commun ; 15(1): 4578, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811586

ABSTRACT

Modulation of the cervix by steroid hormones and commensal microbiome play a central role in the health of the female reproductive tract. Here we describe organ-on-a-chip (Organ Chip) models that recreate the human cervical epithelial-stromal interface with a functional epithelial barrier and production of mucus with biochemical and hormone-responsive properties similar to living cervix. When Cervix Chips are populated with optimal healthy versus dysbiotic microbial communities (dominated by Lactobacillus crispatus and Gardnerella vaginalis, respectively), significant differences in tissue innate immune responses, barrier function, cell viability, proteome, and mucus composition are observed that are similar to those seen in vivo. Thus, human Cervix Organ Chips represent physiologically relevant in vitro models to study cervix physiology and host-microbiome interactions, and hence may be used as a preclinical testbed for development of therapeutic interventions to enhance women's health.


Subject(s)
Cervix Uteri , Host Microbial Interactions , Immunity, Innate , Microbiota , Humans , Female , Cervix Uteri/microbiology , Cervix Uteri/immunology , Microbiota/immunology , Host Microbial Interactions/immunology , Gardnerella vaginalis/immunology , Lactobacillus crispatus/immunology , Mucus/immunology , Mucus/microbiology , Mucus/metabolism , Lab-On-A-Chip Devices
2.
Fish Shellfish Immunol ; 149: 109527, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38561068

ABSTRACT

Skin mucus analysis has recently been used as a non-invasive method to evaluate for fish welfare. The present research study was conducted to examine the skin mucosal immunity and skin microbiota profiles of sturgeons infected with Citrobacter freundii. Our histology results showed that the thickness of the epidermal layer of skin remained thinner, and the number of mucous cells was significantly decreased in sturgeons after infection (p < 0.05). Total protein, alanine aminotransferase, aspartate aminotransferase, superoxide dismutase, and creatine kinase levels in the mucus showed biphasic pattern (decrease and then increase). Lactate dehydrogenase, lysozyme, and acid phosphatase activities in the mucus showed an increasing trend after infection. Furthermore, 16S rRNA sequencing also revealed that C. freundii infection also affected the diversity and community structure of the skin mucus microbiota. An increase in microbial diversity (p > 0.05) and a decrease in microbial abundance (p < 0.05) after infection were noted. The predominant bacterial phyla in the skin mucus were Proteobacteria, Fusobacteria, Bacteroidetes, Firmicutes, and Actinobacteria. Specifically, the relative abundance of Fusobacteria increased after infection. The predominant bacterial genera in the skin mucus were Cetobacterium, Pelomonas, Bradyrhizobium, Flavobacterium, and Pseudomonas. The relative abundance of Cetobacterium, Pseudomonas, and Flavobacterium increased after infection. Our current research findings will provide new insights into the theoretical basis for future research studies exploring the mechanism of sturgeon infection with C. freundii.


Subject(s)
Citrobacter freundii , Enterobacteriaceae Infections , Fish Diseases , Fishes , Immunity, Mucosal , Microbiota , Skin , Animals , Citrobacter freundii/immunology , Microbiota/immunology , Fish Diseases/immunology , Fish Diseases/microbiology , Skin/immunology , Skin/microbiology , Fishes/immunology , Enterobacteriaceae Infections/immunology , Enterobacteriaceae Infections/veterinary , Enterobacteriaceae Infections/microbiology , Mucus/immunology , Mucus/microbiology , RNA, Ribosomal, 16S/genetics
3.
Semin Immunopathol ; 45(4-6): 533-547, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38451292

ABSTRACT

The lungs serve as the primary organ for respiration, facilitating the vital exchange of gases with the bloodstream. Given their perpetual exposure to external particulates and pathogens, they possess intricate protective barriers. Cellular adhesion in the lungs is robustly maintained through tight junctions, adherens junctions, and desmosomes. Furthermore, the pulmonary system features a mucociliary clearance mechanism that synthesizes mucus and transports it to the outside. This mucus is enriched with chemical barriers like antimicrobial proteins and immunoglobulin A (IgA). Additionally, a complex immunological network comprising epithelial cells, neural cells, and immune cells plays a pivotal role in pulmonary defense. A comprehensive understanding of these protective systems offers valuable insights into potential pathologies and their therapeutic interventions.


Subject(s)
Lung , Humans , Lung/immunology , Lung/metabolism , Animals , Mucociliary Clearance , Respiratory Mucosa/immunology , Respiratory Mucosa/metabolism , Tight Junctions/metabolism , Cell Adhesion , Mucus/metabolism , Mucus/immunology
4.
Front Cell Infect Microbiol ; 12: 975173, 2022.
Article in English | MEDLINE | ID: mdl-36004327

ABSTRACT

The human colonic mucus is mainly composed of mucins, which are highly glycosylated proteins. The normal commensal colonic microbiota has mucolytic activity and is capable of releasing the monosaccharides contained in mucins, which can then be used as carbon sources by pathogens such as Enterohemorrhagic Escherichia coli (EHEC). EHEC can regulate the expression of some of its virulence factors through environmental sensing of mucus-derived sugars, but its implications regarding its main virulence factor, Shiga toxin type 2 (Stx2), among others, remain unknown. In the present work, we have studied the effects of five of the most abundant mucolytic activity-derived sugars, Fucose (L-Fucose), Galactose (D-Galactose), N-Gal (N-acetyl-galactosamine), NANA (N-Acetyl-Neuraminic Acid) and NAG (N-Acetyl-D-Glucosamine) on EHEC growth, adhesion to epithelial colonic cells (HCT-8), and Stx2 production and translocation across a polarized HCT-8 monolayer. We found that bacterial growth was maximum when using NAG and NANA compared to Galactose, Fucose or N-Gal, and that EHEC adhesion was inhibited regardless of the metabolite used. On the other hand, Stx2 production was enhanced when using NAG and inhibited with the rest of the metabolites, whilst Stx2 translocation was only enhanced when using NANA, and this increase occurred only through the transcellular route. Overall, this study provides insights on the influence of the commensal microbiota on the pathogenicity of E. coli O157:H7, helping to identify favorable intestinal environments for the development of severe disease.


Subject(s)
Enterohemorrhagic Escherichia coli , Escherichia coli Infections , Escherichia coli O157 , Escherichia coli Proteins , Mucus , Enterohemorrhagic Escherichia coli/metabolism , Escherichia coli Infections/microbiology , Escherichia coli O157/metabolism , Escherichia coli Proteins/metabolism , Expectorants/metabolism , Fucose/metabolism , Galactose , Gastrointestinal Microbiome , Humans , Intestines/metabolism , Intestines/microbiology , Mucins/metabolism , Mucus/immunology , Mucus/metabolism , Shiga Toxin 2/metabolism , Virulence , Virulence Factors/metabolism
5.
Front Immunol ; 13: 895100, 2022.
Article in English | MEDLINE | ID: mdl-35874776

ABSTRACT

Pulmonary diseases represent four out of ten most common causes for worldwide mortality. Thus, pulmonary infections with subsequent inflammatory responses represent a major public health concern. The pulmonary barrier is a vulnerable entry site for several stress factors, including pathogens such as viruses, and bacteria, but also environmental factors e.g. toxins, air pollutants, as well as allergens. These pathogens or pathogen-associated molecular pattern and inflammatory agents e.g. damage-associated molecular pattern cause significant disturbances in the pulmonary barrier. The physiological and biological functions, as well as the architecture and homeostatic maintenance of the pulmonary barrier are highly complex. The airway epithelium, denoting the first pulmonary barrier, encompasses cells releasing a plethora of chemokines and cytokines, and is further covered with a mucus layer containing antimicrobial peptides, which are responsible for the pathogen clearance. Submucosal antigen-presenting cells and neutrophilic granulocytes are also involved in the defense mechanisms and counterregulation of pulmonary infections, and thus may directly affect the pulmonary barrier function. The detailed understanding of the pulmonary barrier including its architecture and functions is crucial for the diagnosis, prognosis, and therapeutic treatment strategies of pulmonary diseases. Thus, considering multiple side effects and limited efficacy of current therapeutic treatment strategies in patients with inflammatory diseases make experimental in vitro and in vivo models necessary to improving clinical therapy options. This review describes existing models for studyying the pulmonary barrier function under acute inflammatory conditions, which are meant to improve the translational approaches for outcome predictions, patient monitoring, and treatment decision-making.


Subject(s)
Lung , Pneumonia , Air Pollutants , Antigen-Presenting Cells/immunology , Antimicrobial Peptides , Chemokines , Cytokines , Granulocytes/immunology , Humans , Lung/immunology , Mucus/immunology
6.
Sci Immunol ; 7(68): eabk2092, 2022 02 04.
Article in English | MEDLINE | ID: mdl-35119941

ABSTRACT

Goblet cells and their main secretory product, mucus, play crucial roles in orchestrating the colonic host-microbe interactions that help maintain gut homeostasis. However, the precise intracellular machinery underlying this goblet cell-induced mucus secretion remains poorly understood. Gasdermin D (GSDMD) is a recently identified pore-forming effector protein that causes pyroptosis, a lytic proinflammatory type of cell death occurring during various pathophysiological conditions. Here, we reveal an unexpected function of GSDMD in goblet cell mucin secretion and mucus layer formation. Specific deletion of Gsdmd in intestinal epithelial cells (ΔIEC) led to abrogated mucus secretion with a concomitant loss of the mucus layer. This impaired colonic mucus layer in GsdmdΔIEC mice featured a disturbed host-microbial interface and inefficient clearance of enteric pathogens from the mucosal surface. Mechanistically, stimulation of goblet cells activates caspases to process GSDMD via reactive oxygen species production; in turn, this activated GSDMD drives mucin secretion through calcium ion-dependent scinderin-mediated cortical F-actin disassembly, which is a key step in granule exocytosis. This study links epithelial GSDMD to the secretory granule exocytotic pathway and highlights its physiological nonpyroptotic role in shaping mucosal homeostasis in the gut.


Subject(s)
Epithelial Cells/immunology , Host Microbial Interactions/immunology , Mucus/immunology , Phosphate-Binding Proteins/immunology , Pore Forming Cytotoxic Proteins/immunology , Animals , Cell Line, Tumor , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Middle Aged
7.
Front Immunol ; 12: 713631, 2021.
Article in English | MEDLINE | ID: mdl-34512636

ABSTRACT

Prophylaxis for and treatment of graft-versus-host disease (GVHD) are essential for successful allogeneic hematopoietic stem cell transplantation (allo-SCT) and mainly consist of immunosuppressants such as calcineurin inhibitors. However, profound immunosuppression can lead to tumor relapse and infectious complications, which emphasizes the necessity of developing novel management strategies for GVHD. Emerging evidence has revealed that tissue-specific mechanisms maintaining tissue homeostasis and promoting tissue tolerance to combat GVHD are damaged after allo-SCT, resulting in exacerbation and treatment refractoriness of GVHD. In the gastrointestinal tract, epithelial regeneration derived from intestinal stem cells (ISCs), a microenvironment that maintains healthy gut microbiota, and physical and chemical mucosal barrier functions against pathogens are damaged by conditioning regimens and/or GVHD. The administration of growth factors for cells that maintain intestinal homeostasis, such as interleukin-22 (IL-22) for ISCs, R-spondin 1 (R-Spo1) for ISCs and Paneth cells, and interleukin-25 (IL-25) for goblet cells, mitigates murine GVHD. In this review, we summarize recent advances in the understanding of GVHD-induced tissue damage and emerging strategies for the management of GVHD.


Subject(s)
Disease Susceptibility , Graft vs Host Disease/etiology , Graft vs Host Disease/metabolism , Animals , Biomarkers , Cellular Microenvironment , Dysbiosis , Gastrointestinal Microbiome , Gene Expression Regulation , Goblet Cells/metabolism , Graft vs Host Disease/pathology , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Mucus/immunology , Mucus/metabolism , Organ Specificity , Signal Transduction , Stem Cells/metabolism , Stem Cells/pathology , Transplantation, Homologous
8.
Fish Shellfish Immunol ; 118: 241-250, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34530078

ABSTRACT

Tools are required for quick and easy preliminary evaluation of functional feeds efficiency on fisheries. The analysis of skin mucus biomarkers is a recent alternative approach providing a faster feed-back from the laboratory which is characterized by being less invasive, more rapid and with reduced costs. The effect of replacing fishmeal and fish protein hydrolysates by means of two porcine by-products, the porcine spray-dried plasma (SDPP) and pig protein hydrolysate (PPH), in compound diets (50.4% crude protein, 16.2% crude protein, 22.1 MJ/kg feed) was evaluated in juvenile meagre (Argyrosomus regius) during a two-months period. To determine the impact of these dietary replacements, growth and food performance were measured together with digestive enzymes activities and filet proximal composition. Additionally, skin mucus was collected and characterized by determining main mucus biomarkers (protein, glucose, lactate, cortisol, and antioxidant capacity) and its antibacterial properties, measured by the quick in vitro co-culture challenges. In comparison to the control group, the inclusion of PPH and SDPP, in meagre diets reduced growth (7.4-8.8% in body weight), increased feed conversion ratios (9.0-10.0%), results that were attributed to a reduction in feed intake values (24.2-33.0%) (P < 0.05). Porcine blood by-products did not modify the activity of gastric and pancreatic digestive enzymes as well as those involved in nutrient absorption (alkaline phosphatase) nor liver oxidative stress condition (P > 0.05). In contrast, a reduction in fillet lipid content associated to an increase in fillet protein levels were found in fish fed SDPP and PPH diets (P < 0.05). As compared to the control diet, the dietary replacement did not alter the levels of the skin mucus biomarkers related to stress (cortisol and antioxidant capacity) or nutritional status (soluble protein, glucose and lactate) (P > 0.05). Interestingly, regardless of the worst performance in somatic growth, meagre fed diets containing both tested porcine by-products showed a significantly improved antibacterial capacity of their skin mucus. This enhancement was more prominent for fish fed with the PPH diet, which may be attributed to a higher content of immunomodulatory bioactive compounds in PPH. Further research will be necessary to provide insights on how the inclusion of SDPP and PPH, at the expense of dietary fishmeal and fish protein hydrolysates, affects feed intake and growth performance in meagre. However, the use of skin mucus biomarkers has been demonstrated to be an excellent methodology for a preliminary characterization of the functional feeds, in particular for their prophylactic properties by the study of mucus antibacterial activity.


Subject(s)
Animal Feed , Anti-Bacterial Agents , Diet , Mucus , Perciformes , Skin , Swine , Animals , Antioxidants , Biomarkers , Diet/veterinary , Glucose , Hydrocortisone , Lactates , Mucus/immunology , Mucus/microbiology , Perciformes/microbiology , Perciformes/physiology , Protein Hydrolysates , Skin/immunology , Skin/microbiology , Swine/blood
9.
Life Sci ; 283: 119871, 2021 Oct 15.
Article in English | MEDLINE | ID: mdl-34352260

ABSTRACT

Non-communicable, chronic respiratory diseases (CRDs) affect millions of individuals worldwide. The course of these CRDs (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) are often punctuated by microbial infections that may result in hospitalization and are associated with increased risk of morbidity and mortality, as well as reduced quality of life. Interleukin-13 (IL-13) is a key protein that regulates airway inflammation and mucus hypersecretion. There has been much interest in IL-13 from the last two decades. This cytokine is believed to play a decisive role in the exacerbation of inflammation during the course of viral infections, especially, in those with pre-existing CRDs. Here, we discuss the common viral infections in CRDs, as well as the potential role that IL-13 plays in the virus-induced disease pathogenesis of CRDs. We also discuss, in detail, the immune-modulation potential of IL-13 that could be translated to in-depth studies to develop IL-13-based therapeutic entities.


Subject(s)
Influenza, Human/immunology , Interleukin-13/immunology , Lung Diseases/immunology , Chronic Disease , Humans , Inflammation/immunology , Inflammation/pathology , Influenza, Human/pathology , Lung Diseases/pathology , Mucus/immunology
10.
Front Immunol ; 12: 692127, 2021.
Article in English | MEDLINE | ID: mdl-34305924

ABSTRACT

Mucus secretion is an important feature of asthma that highly correlates with morbidity. Current therapies, including administration of mucolytics and anti-inflammatory drugs, show limited effectiveness and durability, underscoring the need for novel effective and longer lasting therapeutic approaches. Here we show that mucus production in the lungs is regulated by the TNF superfamily member 15 (TL1A) acting through the mucus-inducing cytokine IL-13. TL1A induces IL13 expression by innate lymphoid cells leading to mucus production, in addition to promoting airway inflammation and fibrosis. Reciprocally, neutralization of IL13 signaling through its receptor (IL4Rα), completely reverses TL1A-induced mucus secretion, while maintaining airway inflammation and fibrosis. Importance of TL1A is further demonstrated using a preclinical asthma model induced by chronic house dust mite exposure where TL1A neutralization by genetic deletion or antagonistic blockade of its receptor DR3 protected against mucus production and fibrosis. Thus, TL1A presents a promising therapeutic target that out benefits IL13 in reversing mucus production, airway inflammation and fibrosis, cardinal features of severe asthma in humans.


Subject(s)
Asthma/immunology , Interleukin-13/immunology , Interleukin-4 Receptor alpha Subunit/immunology , Lung/immunology , Mucus/immunology , Receptors, Tumor Necrosis Factor, Member 25/immunology , Tumor Necrosis Factor Ligand Superfamily Member 15/immunology , Animals , Asthma/pathology , DNA-Binding Proteins/genetics , Female , Fibrosis , Lung/pathology , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptors, Tumor Necrosis Factor, Member 25/genetics , Signal Transduction
11.
Fish Shellfish Immunol ; 116: 107-114, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34256133

ABSTRACT

An eight-week investigation was conducted to access the potential impact of dietary watermelon rind powder (WMRP) and L. plantarum CR1T5 (LP) administered individually or in combination on immunity, disease resistance, and growth rate of Nile tilapia fingerlings cultured in a biofloc system. Three hundred twenty fish (average weight 16.57 ± 0.14 g) were distributed into 16 tanks at a rate of 20 fish per tank. The fish were fed different diets: Diet 1 (0 g kg-1 WMRP and 0 CFU g-1 L. plantarum) (control), Diet 2 (40 g kg-1 WMRP), Diet 3 (108 CFU g-1 LP), and Diet 4 (40 g kg-1 WMRP + 108 CFU g-1 LP) for eight weeks. A completely randomized design (CRD) with four replications was applied. Skin mucus, serum immunity, and growth parameters were analyzed every 4 weeks, and a challenge study against S. agalactiae was conducted at the end of the experiment. The findings showed that the inclusion of WMRP + LP, administrated individually or in a mixture, significantly (P<0.05) stimulated growth, skin mucus, and serum immune parameters of Nile tilapia fingerlings compared with the control. The highest values were detected in fish fed the combination of WMRP and LP, as opposed to individual administration of either WMRP or LP, in which no significant differences were detected. Within the challenge study, the relative percent survival (RPS) in Diet 2, Diet 3, and Diet 4 was 48.0%, 52.0%, and 68.0%, respectively. Fish fed 40 g kg-1 WMRP + LP produced significantly higher RPS and protection against S. agalactiae than the other treated groups. Current results suggest that the dual administration of WMRP and LP maybe an effective feed additive for Nile tilapia grown in an indoor biofloc system, capable of improving growth parameters and increasing resistance to S. agalactiae infection.


Subject(s)
Citrullus , Lactobacillus plantarum , Plant Preparations/pharmacology , Prebiotics , Synbiotics , Animal Feed , Animals , Aquaculture , Cichlids/blood , Cichlids/growth & development , Cichlids/immunology , Diet/veterinary , Disease Resistance , Leukocyte Count , Micrococcus , Mucus/enzymology , Mucus/immunology , Muramidase/immunology , Peroxidase/immunology , Phagocytosis , Powders , Respiratory Burst , Skin/immunology , Streptococcal Infections/prevention & control , Streptococcus agalactiae
12.
Fish Shellfish Immunol ; 117: 320-327, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34246784

ABSTRACT

The polymeric immunoglobulin receptor (pIgR) plays an important role in mediating the transcytosis of polymeric immunoglobulins (pIgs) to protect organisms against pathogen invasion. Here, a polyclonal antibody against grass carp (Ctenopharyngodon idellus) recombinant pIgR was developed by immunizing New Zealand white rabbit, and the responses of pIgR, IgM and IgZ were analyzed after bath immunization and intraperitoneal administration with Flavobacterium columnare. The results showed that pIgR transcription level was similar to IgM and IgZ, but pIgR rose much faster and peaked earlier than IgM and IgZ; the pIgR mRNA levels were higher in the skin and spleen for both immunized groups, while IgM and IgZ mRNA expression were higher in skin, gills, and intestines in bath immersion group, or spleen and head kidney in intraperitoneal immunization group. ELISA revealed that the IgM, IgZ and pIgR protein levels were up-regulated in skin mucus, gill mucus, gut mucus and bile, reaching a higher peak level earlier in skin mucus and gill mucus in bath immersion group, but a higher peak level in bile in injection group. Moreover, secretory component molecules were detected in grass carp's skin, gill and intestine mucus and bile, but not in serum, which molecular mass was near the theoretical mass obtained from the sequence of grass carp pIgR. These results demonstrated that bath and intraperitoneal immunization up-regulated pIgR and secretory Ig expression in secretions, which provided more insights into the role of pIgR in immunity and offer insight into ways of protecting teleost against pathogen invasion.


Subject(s)
Carps/immunology , Fish Diseases/immunology , Fish Proteins/immunology , Flavobacteriaceae Infections/immunology , Flavobacterium , Immunoglobulins/immunology , Animals , Bile/immunology , Carps/microbiology , Flavobacteriaceae Infections/veterinary , Gills/immunology , Mucus/immunology , Rabbits , Recombinant Proteins/immunology , Skin/immunology
13.
J Immunol ; 207(4): 1165-1179, 2021 08 15.
Article in English | MEDLINE | ID: mdl-34330754

ABSTRACT

Increased levels of ambient ozone, one of the six criteria air pollutants, result in respiratory tract injury and worsening of ongoing lung diseases. However, the effect of ozone exposure on the respiratory tract undergoing active lung development and simultaneously experiencing mucoinflammatory lung diseases, such as cystic fibrosis, remains unclear. To address these questions, we exposed Scnn1b transgenic (Scnn1b-Tg+) mice, a mouse model of cystic fibrosis-like lung disease, and littermate wild-type (WT) mice to ozone from postnatal days (PND) 3-20 and examined the lung phenotypes at PND21. As compared with filtered air (FA)-exposed WT mice, the ozone-exposed WT mice exhibited marked alveolar space enlargement, in addition to significant eosinophilic infiltration, type 2 inflammation, and mucous cell metaplasia. Ozone-exposed Scnn1b-Tg+ mice also exhibited significantly increased alveolar space enlargement, which was also accompanied by exaggerated granulocytic infiltration, type 2 inflammation, and a greater degree of mucus obstruction. The alveolar space enlargement in ozone-exposed WT, FA-exposed Scnn1b-Tg+, and ozone-exposed Scnn1b-Tg+ mice was accompanied by elevated levels of MMP12 protein in macrophages and Mmp12 mRNA in the lung homogenates. Finally, although bacterial burden was largely resolved by PND21 in FA-exposed Scnn1b-Tg+ mice, ozone-exposed Scnn1b-Tg+ mice exhibited compromised bacterial clearance, which was also associated with increased levels of IL-10, an immunosuppressive cytokine, and marked mucus obstruction. Taken together, our data show that ozone exposure results in alveolar space remodeling during active phases of lung development and markedly exaggerates the mucoinflammatory outcomes of pediatric-onset lung disease, including bacterial infections, granulocytic inflammation, mucus obstruction, and alveolar space enlargement.


Subject(s)
Bacteria/immunology , Epithelial Sodium Channels/immunology , Inflammation/immunology , Lung/immunology , Ozone/adverse effects , Animals , Cystic Fibrosis/immunology , Disease Models, Animal , Macrophages/immunology , Mice , Mice, Transgenic , Mucus/immunology , Postnatal Care
14.
Int J Mol Sci ; 22(10)2021 May 12.
Article in English | MEDLINE | ID: mdl-34065791

ABSTRACT

Intestinal homeostasis encompasses a complex and balanced interplay among a wide array of components that collaborate to maintain gut barrier integrity. The appropriate function of the gut barrier requires the mucus layer, a sticky cushion of mucopolysaccharides that overlays the epithelial cell surface. Mucus plays a critical anti-inflammatory role by preventing direct contact between luminal microbiota and the surface of the epithelial cell monolayer. Moreover, mucus is enriched with pivotal effectors of intestinal immunity, such as immunoglobulin A (IgA). A fragile and delicate equilibrium that supports proper barrier function can be disturbed by stress. The impact of stress upon intestinal homeostasis results from neuroendocrine mediators of the brain-gut axis (BGA), which comprises a nervous branch that includes the enteric nervous system (ENS) and the sympathetic and parasympathetic nervous systems, as well as an endocrine branch of the hypothalamic-pituitary-adrenal axis. This review is the first to discuss the experimental animal models that address the impact of stress on components of intestinal homeostasis, with special emphasis on intestinal mucus and IgA. Basic knowledge from animal models provides the foundations of pharmacologic and immunological interventions to control disturbances associated with conditions that are exacerbated by emotional stress, such as irritable bowel syndrome.


Subject(s)
Immunoglobulin G/metabolism , Intestinal Mucosa/immunology , Stress, Psychological/immunology , Animals , Homeostasis , Humans , Mucus/immunology
15.
Am J Respir Cell Mol Biol ; 65(6): 581-592, 2021 12.
Article in English | MEDLINE | ID: mdl-34186014

ABSTRACT

The airway epithelium is a central modulator of innate and adaptive immunity in the lung. IL17A expression was found to be increased in the airway epithelium; however, the role of epithelium-derived IL17A in chronic obstructive pulmonary disease (COPD) remains unclear. In this study, we aimed to determine whether epithelium-derived IL17A regulates inflammation and mucus hyperproduction in COPD by using a cultured human bronchial epithelial (HBE) cell line in vitro and an airway epithelium IL17A-specific knockout mouse in vivo. Increased IL17A expression was observed in the mouse airway epithelium upon cigarette smoke (CS) exposure or in a mouse model of COPD that was induced by using CS and Eln (elastin). CS extract (CSE) also triggered IL17A expression in HBE cells. Blocking IL17A or IL17RA (IL17 receptor A) effectively attenuated CSE-induced MUC5AC and the inflammatory cytokines IL6, TNF-α, and IL1ß in HBE cells, suggesting that IL17A mediates CSE-induced inflammation and mucin production in an autocrine manner. CSE activated p-JUN (phospho-JUN) and p-JNK (phospho-c-Jun N-terminal kinase), which were also reduced by IL17RA siRNA, and JUN siRNA attenuated CSE-induced IL6 and MUC5AC. In vivo, selective knockout of IL17A in the airway epithelium markedly reduced the neutrophilic infiltration in BAL fluid, peribronchial inflammation, proinflammatory mediators (CXCL1 [CXC ligand 1] and CXCL2), and mucus production in a COPD mouse model. We showed a novel function of airway epithelium-derived IL17A, which can act locally in an autocrine manner to amplify inflammation and increase mucus production in COPD pathogenesis.


Subject(s)
Cigarette Smoking/immunology , Interleukin-17/immunology , Mucus/immunology , Pulmonary Disease, Chronic Obstructive/immunology , Respiratory Mucosa/immunology , Animals , Cell Line , Cigarette Smoking/genetics , Disease Models, Animal , Humans , Inflammation/genetics , Inflammation/immunology , Interleukin-17/genetics , Mice , Mice, Knockout , Neutrophil Infiltration/genetics , Neutrophils/immunology , Pulmonary Disease, Chronic Obstructive/genetics
17.
Laryngoscope ; 131(9): 2030-2035, 2021 09.
Article in English | MEDLINE | ID: mdl-33710620

ABSTRACT

OBJECTIVES/HYPOTHESIS: To explore the clinically feasible diagnosis criteria and treatment outcomes of allergy-related sialodochitis (ARS). STUDY DESIGN: Prospective Cohort Study. METHODS: Ninety-six consecutive patients were enrolled by the following criteria: 1) recurrent swelling of ≥2 large salivary glands that lasted for ≥3 months; 2) with mucus plug exudations; 3) with atopic diseases; 4) ductal stenosis and/or ectasia. Sixty-four patients with elevation of peripheral blood eosinophil (PBE) and/or serum IgE level comprised group A (highly-suspected ARS group), while the remaining 32 comprised group B (patients without confirmed evidence of ARS). These patients were treated with interventional endoscopy. A chronic obstructive sialadenitis symptom (COSS) questionnaire was used to quantify the treatment outcomes. RESULTS: In group A, Serum IgE was elevated in 84.4% of patients and PBE was elevated in 34.4% of patients. Percentage of submandibular gland involvement was higher in group A than group B (48.4% vs. 18.8%). On sialograms, the snowflake changes of branch ducts were seen in higher percentage of group A compared with group B (59% vs. 35% for parotid glands, 27% vs. 8% for submandibular glands, respectively). Mucus plug smears showed abundant eosinophils in 14 group A patients. Biopsy of five group A patients revealed significant eosinophil infiltration around the main and interlobular ducts. During follow-up, the COSS scores were significantly decreased in both groups, and group B was improved better than group A. CONCLUSION: PBE and serum IgE are important diagnostic indexes of ARS. Mucus plug smear or histopathology verifies the diagnosis. Interventional endoscopy is helpful for ARS cases. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2030-2035, 2021.


Subject(s)
Eosinophilia/blood , Hypersensitivity/complications , Immunoglobulin E/blood , Salivary Ducts/immunology , Sialadenitis/etiology , Adult , Aged , Biopsy , Case-Control Studies , Chronic Disease , Cohort Studies , Endoscopy/methods , Eosinophilia/pathology , Female , Humans , Hypersensitivity/diagnosis , Hypersensitivity/immunology , Male , Middle Aged , Mucus/immunology , Prospective Studies , Salivary Ducts/pathology , Sialadenitis/diagnosis , Sialadenitis/immunology , Sialadenitis/surgery , Sialography/methods , Surveys and Questionnaires , Treatment Outcome
18.
J Allergy Clin Immunol ; 148(2): 450-460, 2021 08.
Article in English | MEDLINE | ID: mdl-33675819

ABSTRACT

BACKGROUND: Integrated care pathways improve the management of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). The application of integrated care pathways requires development of endotype-based biomarkers to stratify patients. The value of cytokines and markers induced by cytokines for the management of CRSwNP is largely unknown. OBJECTIVES: Our aim was to determine the prognostic and pharmacologic value of type 2, non-type 2 cytokines, and markers associated with type 2 inflammation, including CCL26, periostin, and cystatin SN, in nasal secretions for CRSwNP. METHODS: This retrospective study assigned 151 patients with CRSwNP to the discovery and validation phases. Concentrations of cytokines, CCL26, periostin, and cystatin SN in nasal secretions were determined by using Luminex and ELISA. Predictive significance was assessed with receiver-operating characteristic curves. Survival analysis was performed by using Kaplan-Meier curves and Cox regression models. RESULTS: Cystatin SN was an independent predictor of the uncontrolled status of CRSwNP over a 2-year follow-up after adjustment for other risk factors (hazard ratio = 1.168 and 1.132 in the discovery and validation phases, respectively; both P < .001). Patients with high cystatin SN concentrations presented with a faster onset and higher rate of uncontrolled status than did those with low levels (P < .001). Enhanced medical treatment for patients with high cystatin SN levels postponed the uncontrolled status in the discovery (P = .016) and validation (P = .002) phases but did not completely abolish it by the end of the follow-up. CONCLUSION: Cystatin SN levels in nasal secretions hold strong prognostic value and can facilitate medical instructions for managing CRSwNP.


Subject(s)
Mucus , Nasal Polyps , Rhinitis , Salivary Cystatins , Sinusitis , Adult , Biomarkers/metabolism , Chronic Disease , Female , Follow-Up Studies , Humans , Male , Middle Aged , Mucus/immunology , Mucus/metabolism , Nasal Polyps/diagnosis , Nasal Polyps/drug therapy , Nasal Polyps/immunology , Nasal Polyps/metabolism , Prognosis , Retrospective Studies , Rhinitis/diagnosis , Rhinitis/drug therapy , Rhinitis/immunology , Rhinitis/metabolism , Salivary Cystatins/immunology , Salivary Cystatins/metabolism , Sinusitis/diagnosis , Sinusitis/drug therapy , Sinusitis/immunology , Sinusitis/metabolism
19.
Int Immunopharmacol ; 94: 107488, 2021 May.
Article in English | MEDLINE | ID: mdl-33640857

ABSTRACT

MicroRNA-181b (miR-181b) has been well noted with anti-inflammatory properties in several pathological conditions. It has also been suggested to be downregulated in patients with asthma. In this study, we explored the function of miR-181b in airway remodeling in asthmatic mice and the molecular mechanism. A mouse model with asthma was induced by ovalbumin (OVA) challenge, and miR-181b was found to be downregulated in lung tissues in the OVA-challenged mice. Overexpression of miR-181b was introduced in mice, after which the respiratory resistance, inflammatory infiltration, mucus production, and epithelial-mesenchymal transition (EMT) and fibrosis in mouse airway tissues were decreased. The integrated bioinformatics analysis suggested long non-coding RNA (lncRNA) TUG1 as a sponge for miR-181b. miR-181 directly targeted high mobility group box 1 (HMGB1) mRNA. HMGB1 was suggested to enhance activation of the nuclear factor kappa B (NF-κB) signaling. Further upregulation of lncRNA TUG1 blocked the protective functions of miR-181b in asthmatic mice. To conclude, this study evidenced that lncRNA TUG1 reinforces HMGB1 expression through sequestering microRNA-181b, which activates the NF-κB signaling pathway and promotes airway remodeling in asthmatic mice. This study may provide novel ideas in asthma management.


Subject(s)
Airway Remodeling/immunology , Asthma/immunology , HMGB1 Protein/immunology , MicroRNAs/immunology , RNA, Long Noncoding/immunology , Airway Remodeling/genetics , Allergens , Animals , Asthma/genetics , Asthma/pathology , Cells, Cultured , Disease Models, Animal , Female , HMGB1 Protein/genetics , Lung/pathology , Mice, Inbred BALB C , Mucus/immunology , NF-kappa B/immunology , Ovalbumin , Signal Transduction
20.
Fish Shellfish Immunol ; 111: 170-178, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33561561

ABSTRACT

Extracellular vesicles play a regulatory role in intracellular and intercellular transmission through a variety of biological information molecules, including mRNA, small RNAs and proteins. piRNAs are one kind of regulatory small RNAs in the vesicles at the post transcriptional level. Hereby, we isolated the extracellular vesicles from skin mucus and screened the piRNA profiles of these vesicles, aiming at developing biomarkers related to bacterial infections in Cynoglossus semilaevis. The different profilings of piRNAs in mucous extracellular vesicles of C. semilaevis were compared through small RNA sequencing, between fish infected with Vibrio harveyi and healthy ones. The number of clean reads on the alignment of exosome sick (ES) group was 105, 345 and that of exosome control (EC) group was 455, 144. GO and KEGG pathway enrichment analysis showed that most of the target genes were involved in cellular process, response to stimulus, biological regulation, immune system process and signal transduction, signal molecular and interaction, transport and catabolism. The 45 final candidate piRNAs related to immunity or infectious diseases included 20 piRNAs with high expression in the ES group and 25 piRNAs with a low expression in the ES group. After verification by qRT-PCR, there was significant difference of five piRNAs expression level between infected fish and healthy fish, in line with the sequencing. The expression level of piR-mmu-16401212, piR-mmu-26829319 and piR-gga-244092 in infected fish were significantly lower than that of control group, while piR-gga-71717 and piR-gga-99034 were higher, which implying that these piRNAs in mucous extracellular vesicles can be used to identify diseased fish from normal ones. This work supplied a novel class of biomarker for infection diagnosis in fish, and it will be benefit for screening disease resistant breeding of C. semilaevis.


Subject(s)
Fish Diseases/diagnosis , Flatfishes/immunology , Gene Expression , RNA, Small Interfering/genetics , Vibrio Infections/veterinary , Animals , Biomarkers/metabolism , Exosomes/genetics , Extracellular Vesicles/metabolism , Fish Diseases/immunology , Fish Diseases/microbiology , Flatfishes/genetics , Mucus/immunology , Mucus/metabolism , Skin/immunology , Vibrio/physiology , Vibrio Infections/diagnosis , Vibrio Infections/immunology , Vibrio Infections/microbiology
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