scholarly journals Pathogenesis and Persistence of Increased Epithelial Mucosubstances in the Nasal Airways of Rats and Mice Episodically Exposed to Ethylene

2020 ◽  
Vol 48 (7) ◽  
pp. 875-886
Author(s):  
Jack R. Harkema ◽  
Elyse A. Eldridge ◽  
Amy Freeland ◽  
Daven Jackson-Humbles ◽  
Ryan A. Lewandowski ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mucous Cell ◽  
Airway Disease ◽  
Lymphoid Cells ◽  
Nasal Airway ◽  
Cell Hyperplasia ◽  
Mucus Production ◽  
Nasal Airways ◽  
Rats And Mice ◽  
Deficient Mice

Rats repeatedly exposed to high airborne concentrations of ethylene develop eosinophilic rhinitis and mucous cell hyperplasia/hypertrophy (MCH) in nasal respiratory epithelium. Mechanisms underlying these lesions are not well understood to inform occupational exposure guidelines. In this study, we determined (1) the nasal histopathology in rats episodically exposed to ethylene, (2) the ethylene-induced nasal histopathology in similarly exposed mice, and (3) how innate lymphoid cells (ILCs) play a role in ethylene-induced MCH. Animals were exposed to 0 or 10,000 ppm ethylene, 6 h/d, 5 d/wk, for 2 weeks and sacrificed 1 day or 2 weeks postexposure. Others received three 2-week exposure blocks separated by 2-week intervals of no exposure. Episodic exposure was chosen to aid in distinguishing irritant from immune responses. Mucous cell hyperplasia/hypertrophy was induced by ethylene in both species. Rats developed a mild, but transient, eosinophilic rhinitis. Mucous cell hyperplasia/hypertrophy was transient in mice, but persistent in rats. Increases in epithelial mucosubstances after 2 weeks of exposure were only present in ILC-sufficient mice, but not in ILC-deficient mice suggesting that ILCs play a role in MCH and overexpression of genes associated with mucus production/secretion. These findings in animals suggest that inhaled ethylene does not act as a sensitizing agent and will not induce allergen-like nasal airway disease.

scholarly journals Maintenance of Type 2 Response by CXCR6-Deficient ILC2 in Papain-Induced Lung Inflammation

2019 ◽  
Vol 20 (21) ◽  
pp. 5493 ◽  
Author(s):  
Meunier ◽  
Chea ◽  
Garrido ◽  
Perchet ◽  
Petit ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Inflammatory Conditions ◽  
Airway Diseases ◽  
Type 2 Cytokines ◽  
Lymphoid Organogenesis ◽  
Deficient Mice

Innate lymphoid cells (ILC) are important players of early immune defenses in situations like lymphoid organogenesis or in case of immune response to inflammation, infection and cancer. Th1 and Th2 antagonism is crucial for the regulation of immune responses, however mechanisms are still unclear for ILC functions. ILC2 and NK cells were reported to be both involved in allergic airway diseases and were shown to be able to interplay in the regulation of the immune response. CXCR6 is a common chemokine receptor expressed by all ILC, and its deficiency affects ILC2 and ILC1/NK cell numbers and functions in lungs in both steady-state and inflammatory conditions. We determined that the absence of a specific ILC2 KLRG1+ST2– subset in CXCR6-deficient mice is probably dependent on CXCR6 for its recruitment to the lung under inflammation. We show that despite their decreased numbers, lung CXCR6-deficient ILC2 are even more activated cells producing large amount of type 2 cytokines that could drive eosinophilia. This is strongly associated to the decrease of the lung Th1 response in CXCR6-deficient mice.

scholarly journals Dietary Selenium in Immune Mechanisms During an Enteric Bacterial Infection (OR12-08-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Shaneice Nettleford ◽  
Luming Zhao ◽  
James Fraser ◽  
Adwitia Dey ◽  
Dhimant Desai ◽  
...  
Keyword(s):  
Immune Responses ◽  
Trace Element ◽  
Lymphoid Cells ◽  
Nutritional Deficiencies ◽  
Enteric Infection ◽  
Bacterial Burden ◽  
Citrobacter Rodentium ◽  
T Helper 17 ◽  
Western Blots ◽  
Deficient Mice

Abstract Objectives Enteropathogenic Escherichia coli (EPEC) poses a great threat to developing countries, as EPEC can result in diarrhea and colitis in children. Interestingly, the effect of trace element nutritional deficiencies as well as their supplementation on disease pathogenesis is increasingly being recognized. We have previously reported that supplementation of mice with selenium (Se), a trace element that is incorporated into selenoproteins as the 21st amino acid, resulted in the amelioration of chemically induced colitis through the downregulation of pro-inflammatory mediators of the arachidonic acid pathway, including prostaglandin E2 (PGE2). Here we examined the effects of Se supplementation on immune responses during an enteric infection with Citrobacter rodentium, a natural murine enteropathogen. Methods C57BL/6 mice placed on Se-deficient (0.01 ppm Se), Se-adequate (0.08 ppm Se), or Se-supplemented (0.4 ppm Se) diets for 8 weeks were infected with Citrobacter rodentium, the murine equivalent of EPEC with a shared core set of virulence factors. Mice were euthanized, and colons were collected for further analysis including western blots and flow cytometry. Results Se-deficient mice experienced increased bacterial burden, mortality, and decreased colon length following infection, compared to Se-adequate and Se-supplemented mice. Studies revealed that there was an increase type 3 innate-lymphoid cells (ILC3s) and IL-22 producing T helper 17 (Th17) cells, but a decrease in regulatory T- cells (Tregs) and 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that preferentially oxidizes PGE2, in the colon of Se-deficient mice compared to Se-adequate and Se-supplemented mice. Treatment of Se-adequate mice with CAY10397, an inhibitor of 15-PGDH, increased the bacterial burden following infection. Infection of mice that lack expression of selenoproteins in macrophages (Trspfl/fl LysMCre) showed increased mortality despite being fed diets replete with Se. Conclusions Adequate to supplemental levels of dietary Se is required to maximize the expression of selenoproteins to effectively mediate resolution of enteric infections. Selenoproteins act through diverse mechanisms, including modulation of immune responses and inflammation through the oxidative metabolism of PGE2. Funding Sources National Institute of Health.

scholarly journals Mucin granules are degraded in the autophagosome-lysosome pathway as a means of resolving airway mucous cell metaplasia

2020 ◽  
Author(s):  
JM Sweeter ◽  
K Kudrna ◽  
K Hunt ◽  
P Thomes ◽  
BF Dickey ◽  
...  
Keyword(s):  
Mucous Cell ◽  
Airway Disease ◽  
Airway Epithelial Cells ◽  
Secretory Cells ◽  
Airway Epithelial ◽  
Mtor Inhibition ◽  
Airway Diseases ◽  
Obstructive Airway Diseases ◽  
Deficient Mice

AbstractExacerbations of muco-obstructive airway diseases such as COPD and asthma are associated with epithelial changes termed mucous cell metaplasia (MCM). The molecular pathways triggering MCM have been identified; however, the factors that regulate resolution are less well understood. We hypothesized that the autophagosome-lysosome pathway is required for resolution of MCM by degrading cytoplasmic mucins. We found increased intracellular levels of Muc5ac and Muc5b in autophagy-deficient mice. This difference was not due to defective mucin secretion. Instead, we found that Lamp1-labeled lysosomes surrounded mucin granules of mucous cells indicating that granules were being degraded. Using a model of resolution of mucous cell metaplasia in mice, we found increased lysosomal proteolytic activity that peaked in the days after inflammation. Autophagy-deficient mice had persistent accumulation of mucin granules that failed to decline due to reduced mucin degradation. We applied these findings in vitro to human airway epithelial cells (AECs). Activation of autophagy by mTOR inhibition led to degradation of mucin granules in AECs. Our findings indicate that during peak and resolution phases of MCM, mucin granules can be degraded by autophagy. The addition of mucin degradation to the existing paradigm of production and secretion may more fully explain how the secretory cells handle excess amounts of cytoplasmic mucin and offers a therapeutic target to speed resolution of MCM in airway disease exacerbations.Abstract Figure

scholarly journals Airway-associated macrophages in homeostasis and repair

2020 ◽  
Author(s):  
Anna E. Engler ◽  
Alexandra B. Ysasi ◽  
Riley M.F. Pihl ◽  
Carlos Villacorta-Martin ◽  
Hailey M. Heston ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Airway Disease ◽  
Lymphoid Cells ◽  
Epithelial Injury ◽  
Cell Behaviors ◽  
Injury Repair ◽  
Single Cell Rna Sequencing ◽  
Group 2 ◽  
Conducting Airways ◽  
Deficient Mice

SummaryThere is an increasing appreciation for the heterogeneity of myeloid lineages in the respiratory system, but whether distinct populations associate with the conducting airways remains unknown. We use single cell RNA sequencing, flow cytometry and immunofluorescence to characterize myeloid cells of the mouse trachea during homeostasis and epithelial injury/repair. We identify submucosal macrophages that are similar to lung interstitial macrophages and intraepithelial macrophages, and find that repair of the tracheal epithelium is impaired in Ccr2-deficient mice. Following injury there are early increases in neutrophils and submucosal macrophages, including M2-like macrophages. Unexpectedly, intraepithelial macrophages are initially lost but later replaced from CCR2+ monocytes. Mast cells and group 2 innate lymphoid cells are sources of IL13 that polarizes macrophages and directly influences basal cell behaviors. Their proximity to the airway epithelium establishes these myeloid populations as potential therapeutic targets for airway disease.

scholarly journals Nasal alum-adjuvanted vaccine promotes IL-33 release from alveolar epithelial cells that elicits IgA production via type 2 immune responses

2021 ◽  
Vol 17 (8) ◽  
pp. e1009890
Author(s):  
Eita Sasaki ◽  
Hideki Asanuma ◽  
Haruka Momose ◽  
Keiko Furuhata ◽  
Takuo Mizukami ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Immune Responses ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cultured Cells ◽  
Alveolar Epithelial Cell ◽  
Lymphoid Cells ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Deficient Mice

Aluminum hydroxide salts (alum) have been added to inactivated vaccines as safe and effective adjuvants to increase the effectiveness of vaccination. However, the exact cell types and immunological factors that initiate mucosal immune responses to alum adjuvants are unclear. In this study, the mechanism of action of alum adjuvant in nasal vaccination was investigated. Alum has been shown to act as a powerful and unique adjuvant when added to a nasal influenza split vaccine in mice. Alum is cytotoxic in the alveoli and stimulates the release of damage-associated molecular patterns, such as dsDNA, interleukin (IL)-1α, and IL-33. We found that Ag-specific IgA antibody (Ab) production was markedly reduced in IL-33-deficient mice. However, no decrease was observed in Ag-specific IgA Ab production with DNase I treatment, and no decrease was observed in IL-1α/β or IL-6 production in IL-33-deficient mice. From the experimental results of primary cultured cells and immunofluorescence staining, although IL-1α was secreted by alveolar macrophage necroptosis, IL-33 release was observed in alveolar epithelial cell necroptosis but not in alveolar macrophages. Alum- or IL-33-dependent Ag uptake enhancement and elevation of OX40L expression were not observed. By stimulating the release of IL-33, alum induced Th2 immunity via IL-5 and IL-13 production in group 2 innate lymphoid cells (ILC2s) and increased MHC class II expression in antigen-presenting cells (APCs) in the lung. Our results suggest that IL-33 secretion by epithelial cell necroptosis initiates APC- and ILC2-mediated T cell activation, which is important for the enhancement of Ag-specific IgA Ab production by alum.

scholarly journals Inhibition of B-cell death does not restore T-cell-dependent immune responses in CD40-deficient mice

Immunology ◽  
2003 ◽  
Vol 109 (4) ◽  
pp. 504-509
Author(s):  
Jesus Merino ◽  
Miguel A. Diez ◽  
Maria Muniz ◽  
Luis Buelta ◽  
Gabriel Nunez ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Deficient Mice

scholarly journals A role for CD9 molecules in T cell activation.

1996 ◽  
Vol 184 (2) ◽  
pp. 753-758 ◽  
Author(s):  
X G Tai ◽  
Y Yashiro ◽  
R Abe ◽  
K Toyooka ◽  
C R Wood ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Expression Cloning ◽  
Wild Type ◽  
Almost All ◽  
Antigen Presenting ◽  
Deficient Mice

Costimulation mediated by the CD28 molecule plays an important role in optimal activation of T cells. However, CD28-deficient mice can mount effective T cell-dependent immune responses, suggesting the existence of other costimulatory systems. In a search for other costimulatory molecules on T cells, we have developed a monoclonal antibody (mAb) that can costimulate T cells in the absence of antigen-presenting cells (APC). The molecule recognized by this mAb, 9D3, was found to be expressed on almost all mature T cells and to be a protein of approximately 24 kD molecular mass. By expression cloning, this molecule was identified as CD9, 9D3 (anti-CD9) synergized with suboptimal doses of anti-CD3 mAb in inducing proliferation by virgin T cells. Costimulation was induced by independent ligation of CD3 and CD9, suggesting that colocalization of these two molecules is not required for T cell activation. The costimulation by anti-CD9 was as potent as that by anti-CD28. Moreover, anti-CD9 costimulated in a CD28-independent way because anti-CD9 equally costimulated T cells from the CD28-deficient as well as wild-type mice. Thus, these results indicate that CD9 serves as a molecule on T cells that can deliver a potent CD28-independent costimulatory signal.

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