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BACKGROUNDMucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.METHODSUsing histology and spatial, single-cell proteomics, we characterized mucus-plugged airways from nontransplantable donor lungs of 14 patients with asthma (9 with fatal asthma and 5 with nonfatal asthma) and individuals acting as controls (10 with chronic obstructive pulmonary disease and 14 free of lung disease). Additionally, we used an airway epithelial cell-eosinophil (AEC-eosinophil) coculture model to explore how AEC mucus affects eosinophil degranulation.RESULTSAsthma mucus plugs were tethered to airways showing infiltration with innate lymphoid type 2 cells and hyperplasia of smooth muscle cells and MUC5AC-expressing goblet cells. Asthma mucus plugs were infiltrated with immune cells that were mostly dual positive for eosinophil peroxidase (EPX) and neutrophil elastase, suggesting that neutrophils internalize EPX from degranulating eosinophils. Indeed, eosinophils exposed to mucus from IL-13-activated AECs underwent CD11b- and glycan-dependent cytolytic degranulation. Dual-positive granulocytes varied in frequency in mucus plugs. Whereas paucigranulocytic plugs were MUC5AC rich, granulocytic plugs had a mix of MUC5AC, MUC5B, and extracellular DNA traps. Paucigranulocytic plugs occurred more frequently in (acute) fatal asthma and granulocytic plugs predominated in (chronic) nonfatal asthma.CONCLUSIONTogether, our data suggest that mucin-rich mucus plugs in fatal asthma form because of acute goblet cell degranulation in remodeled airways and that granulocytic mucus plugs in chronic asthma persist because of a sustaining niche characterized by epithelial cell-mucin-granulocyte cross-talk.FUNDINGNIH grants HL080414, HL107202, and AI077439.

Purpose To evaluate changes in corneal sensitivity, tear film function, and ocular surface stability in patients after cataract surgery. Methods This hospital-based prospective randomized trial included 48 eyes from 30 patients who underwent phacoemulsification. Slit-lamp examination, Schirmer test 1 (ST1), and measurement of corneal sensitivity and tear film breakup time (BUT) were performed for all patients 1 day before and 1 day, 1 month, and 3 months after surgery. In addition, conjunctival impression cytology from the temporal region of the conjunctiva was simultaneously performed. Results Corneal sensitivity at the center and temporal incision sites had decreased significantly at 1 day postoperatively ( P  = .021, P  < .001). However, the sensitivity had returned to almost the preoperative level 1 month postoperatively. The mean postoperative ST1 results were no different from preoperative values. On the other hand, BUT results had decreased significantly at 1 day postoperatively ( P  = .01) but had returned to almost the preoperative level 1 month postoperatively. Mean goblet cell density (GCD) had decreased significantly at 1 day, 1 month, and 3 months postoperatively ( P  < .001). In addition, decrease in GCD and cataract operative time were highly correlated ( r 2  = 0.65). Conclusions The decrease in GCD, which was correlated with operative time, had not recovered at 3 months after cataract surgery. Therefore, microscopic ocular surface damage during cataract surgery seems to be one of the pathogenic factors that cause ocular discomfort and dry eye syndrome after cataract surgery.

The aim of this study was to evaluate the goblet cell density (GCD) of conjunctiva in medically-controlled glaucoma using laser scanning confocal microscopy (LSCM). Fifty-five glaucomatous patients were enrolled and divided into two groups: Group 1 (27 eyes), controlled with one medication; and group 2 (28 eyes), controlled with two medications. Seventeen patients with dry eye disease (DED) and 17 healthy individuals served as controls. Patients completed the Ocular Surface Disease Index (OSDI) questionnaire and underwent determination of tear film break-up time (BUT), corneal staining, and Schirmer test I. For the GCD assessment, 12 high-quality images were acquired from the upper conjunctival epithelium (superior nasal, superior central, and superior temporal sectors). Overall, GCD was significantly reduced in both glaucoma groups and those with DED compared to healthy controls (p<0.001), with values markedly lower in group 2 compared to group 1 (p<0.05). GCD was not significantly different between those with DED and group 2. A significant negative correlation was found of GCD with OSDI and with BUT (p<0.001; R=-0.795 and R=-0.756, respectively). Glaucoma therapy leads to a marked reduction of GCs, especially in the associative regimens. Given the negative correlation with tear film function tests, GCD reduction may play a pivotal role in the pathophysiology of the glaucoma-related disease of the ocular surface.

The colonic epithelium facilitates host–microorganism interactions to control mucosal immunity, coordinate nutrient recycling and form a mucus barrier. Breakdown of the epithelial barrier underpins inflammatory bowel disease (IBD). However, the specific contributions of each epithelial-cell subtype to this process are unknown. Here we profile single colonic epithelial cells from patients with IBD and unaffected controls. We identify previously unknown cellular subtypes, including gradients of progenitor cells, colonocytes and goblet cells within intestinal crypts. At the top of the crypts, we find a previously unknown absorptive cell, expressing the proton channel OTOP2 and the satiety peptide uroguanylin, that senses pH and is dysregulated in inflammation and cancer. In IBD, we observe a positional remodelling of goblet cells that coincides with downregulation of WFDC2—an antiprotease molecule that we find to be expressed by goblet cells and that inhibits bacterial growth. In vivo, WFDC2 preserves the integrity of tight junctions between epithelial cells and prevents invasion by commensal bacteria and mucosal inflammation. We delineate markers and transcriptional states, identify a colonic epithelial cell and uncover fundamental determinants of barrier breakdown in IBD. Profiling of single epithelial cells in healthy and inflamed colons identifies specialized cellular subpopulations, including a type of goblet cell that secretes the antibacterial protein WFDC2, which preserves the integrity of the epithelial barrier layer.

The intestinal tract faces numerous challenges that require several layers of defence. The tight epithelium forms a physical barrier that is further protected by a mucus layer, which provides various site-specific protective functions. Mucus is produced by goblet cells, and as a result of single-cell RNA sequencing identifying novel goblet cell subpopulations, our understanding of their various contributions to intestinal homeostasis has improved. Goblet cells not only produce mucus but also are intimately linked to the immune system. Mucus and goblet cell development is tightly regulated during early life and synchronized with microbial colonization. Dysregulation of the developing mucus systems and goblet cells has been associated with infectious and inflammatory conditions and predisposition to chronic disease later in life. Dysfunctional mucus and altered goblet cell profiles are associated with inflammatory conditions in which some mucus system impairments precede inflammation, indicating a role in pathogenesis. In this Review, we present an overview of the current understanding of the role of goblet cells and the mucus layer in maintaining intestinal health during steady-state and how alterations to these systems contribute to inflammatory and infectious disease.Mucus, produced by goblet cells, provides the intestinal tract with an additional layer of protection. This Review discusses the role of mucus and goblet cells in intestinal health and disease, and dissects the underlying regulatory mechanisms.

Barrett’s oesophagus—a metaplasia that can be induced by persistent acid reflux, and predisposes patients to oesophageal cancer—arises from a population of basal cells at the gastro-oesophageal junction. Cells cross the junction of throat cancer Barrett's metaplasia occurs at the gastro-oesophageal junction, sometimes as a result of persistent acid reflux, and predisposes patients to oesophageal cancer. There has been some debate over which cells generate Barrett's oesophagus. Jianwen Que and colleagues now identify a population of basal cells at the gastro-oesophageal junction that give rise to Barrett's metaplasia in mice. Data from human samples suggest the same population of cells gives rise to Barrett's metaplasia in humans. In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy 1 , 2 , 3 , but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown 1 , 2 , 3 . In the case of Barrett’s oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells 4 . On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett’s oesophagus in terms of the presence of intestinal goblet cells 5 , 6 , 7 , 8 . Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63 + KRT5 + KRT7 + ) at the squamous–columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous–columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett’s metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett’s oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63 + KRT5 + KRT7 + basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett’s oesophagus.

The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that succinate receptor 1 (Sucnr1) is specifically expressed in tuft cells. Thus, we hypothesized that the succinate–Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here we confirmed that Sucnr1 is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency (Sucnr1 −/−) showed diminished immune responses to treatment with polyethylene glycol and streptomycin, which are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm Nippostrongylus brasiliensis that also produces succinate. Thus, Sucnr1 is required for microbiota-induced but not for a generalized worm-induced type 2 immunity.

Background: The intestinal mucus layer plays a key role in the maintenance of host-microbiota homeostasis. To document the crosstalk between the host and microbiota, we used gnotobiotic models to study the influence of two major commensal bacteria, Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii, on this intestinal mucus layer. B. thetaiotaomicron is known to use polysaccharides from mucus, but its effect on goblet cells has not been addressed so far. F. prausnitzii is of particular physiological importance because it can be considered as a sensor and a marker of human health. We determined whether B. thetaiotaomicron affected goblet cell differentiation, mucin synthesis and glycosylation in the colonic epithelium. We then investigated how F. prausnitzii influenced the colonic epithelial responses to B. thetaiotaomicron.[br/] Results: B. thetaiotaomicron, an acetate producer, increased goblet cell differentiation, expression of mucus-related genes and the ratio of sialylated to sulfated mucins in mono-associated rats. B. thetaiotaomicron, therefore, stimulates the secretory lineage, favoring mucus production. When B. thetaiotaomicron was associated with F. prausnitzii, an acetate consumer and a butyrate producer, the effects on goblet cells and mucin glycosylation were diminished. F. prausnitzii, by attenuating the effects of B. thetaiotaomicron on mucus, may help the epithelium to maintain appropriate proportions of different cell types of the secretory lineage. Using a mucus-producing cell line, we showed that acetate up-regulated KLF4, a transcription factor involved in goblet cell differentiation.[br/] Conclusions: B. thetaiotaomicron and F. prausnitzii, which are metabolically complementary, modulate, in vivo, the intestinal mucus barrier by modifying goblet cells and mucin glycosylation. Our study reveals the importance of the balance between two main commensal bacteria in maintaining colonic epithelial homeostasis via their respective effects on mucus.

Pulmonary neuroendocrine cells (PNECs) are a rare cell type located in airway and alveolar epithelia and are often in contact with sensory nerve fibers. They have a wide phylogenic distribution and are found even in the relatively primitive lungs of amphibia and reptiles, suggesting a critical function. Sui et al. found that mice lacking PNECs have suppressed type 2 (allergic) immune responses. PNECs were observed in close proximity to group 2 innate lymphoid cells (ILC2s) around airway branch points. The PNECs enhanced ILC2 activity by secreting CGRP (calcitonin gene-related peptide). They also induced goblet-cell hyperplasia via the neurotransmitter GABA (γ-aminobutyric acid). Interestingly, human asthma patients were found to have increased PNEC numbers, suggesting a potential therapeutic target for the treatment of asthma. Science , this issue p. eaan8546 PNECs, a rare population of cells in the airways, are critical for amplifying the airway allergen signal into mucosal responses in the lungs. Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that Ascl1 -mutant mice that have no PNECs exhibit severely blunted mucosal type 2 response in models of allergic asthma. PNECs reside in close proximity to group 2 innate lymphoid cells (ILC2s) near airway branch points. PNECs act through calcitonin gene-related peptide (CGRP) to stimulate ILC2s and elicit downstream immune responses. In addition, PNECs act through the neurotransmitter γ-aminobutyric acid (GABA) to induce goblet cell hyperplasia. The instillation of a mixture of CGRP and GABA in Ascl1 -mutant airways restores both immune and goblet cell responses. In accordance, lungs from human asthmatics show increased PNECs. These findings demonstrate that the PNEC-ILC2 neuroimmunological modules function at airway branch points to amplify allergic asthma responses.

Although spontaneous protein crystallization is a rare event in vivo, Charcot-Leyden crystals (CLCs) consisting of galectin-10 (Gal10) protein are frequently observed in eosinophilic diseases, such as asthma. We found that CLCs derived from patients showed crystal packing and Gal10 structure identical to those of Gal10 crystals grown in vitro. When administered to the airways, crystalline Gal10 stimulated innate and adaptive immunity and acted as a type 2 adjuvant. By contrast, a soluble Gal10 mutein was inert. Antibodies directed against key epitopes of the CLC crystallization interface dissolved preexisting CLCs in patient-derived mucus within hours and reversed crystal-driven inflammation, goblet-cell metaplasia, immunoglobulin E (IgE) synthesis, and bronchial hyperreactivity (BHR) in a humanized mouse model of asthma. Thus, protein crystals may promote hallmark features of asthma and are targetable by crystal-dissolving antibodies.