MrgprA3 neurons drive cutaneous immunity against helminths through selective control of myeloid-derived IL-33.

Skin uses interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. Herein, we demonstrate that the human parasitic helminth Schistosoma mansoni inhibited pruritus evoked by itch-sensing afferents bearing the Mas-related G-protein-coupled receptor A3 (MrgprA3) in mice. MrgprA3 neurons controlled interleukin (IL)-17+ γδ T cell expansion, epidermal hyperplasia and host resistance against S. mansoni through shaping cytokine expression in cutaneous antigen-presenting cells. MrgprA3 neuron activation downregulated IL-33 but induced IL-1ß and tumor necrosis factor in macrophages and type 2 conventional dendritic cells partially through the neuropeptide calcitonin gene-related peptide. Macrophages exposed to MrgprA3-derived secretions or bearing cell-intrinsic IL-33 deletion showed increased chromatin accessibility at multiple inflammatory cytokine loci, promoting IL-17/IL-23-dependent changes to the epidermis and anti-helminth resistance. This study reveals a previously unrecognized intercellular communication mechanism wherein itch-inducing MrgprA3 neurons initiate host immunity against skin-invasive parasites by directing cytokine expression patterns in myeloid antigen-presenting cell subsets.

The Secretome of Adult Murine Hookworms Is Shaped by Host Expression of STAT6.

Co-evolutionary adaptation of hookworms with their mammalian hosts has been selected for immunoregulatory excretory/secretory (E/S) products. However, it is not known whether, or if so, how host immunological status impacts the secreted profile of hematophagous adult worms. This study interrogated the impact of host Signal transducer and activator of transcription 6 (STAT6) expression during the experimental evolution of hookworms through the sequential passage of the life cycle in either STAT6 deficient or WT C57BL/6 mice. Proteomic analysis of E/S products by LC-MS showed increased abundance of 15 proteins, including myosin-3, related to muscle function, and aconitate hydratase, related to iron homeostasis. However, most E/S proteins (174 of 337 unique identities) were decreased, including those in the Ancylostoma-secreted protein (ASP) category, and metallopeptidases. Several identified proteins are established immune-modulators such as fatty acid-binding protein homologue, cystatin, and acetylcholinesterase. Enrichment analysis of InterPro functional categories showed down-regulation of Cysteine-rich secretory proteins, Antigen 5, and Pathogenesis-related 1 proteins (CAP), Astacin-like metallopeptidase, Glycoside hydrolase, and Transthyretin-like protein groups in STAT6 KO-adapted worms. Taken together, these data indicate that in an environment lacking Type 2 immunity, hookworms alter their secretome by reducing immune evasion proteins- and increasing locomotor- and feeding-associated proteins.

Oncolytic Myxoma virus infects and damages the tegument of the human parasitic flatworm Schistosoma mansoni.

Schistosomiasis is a devastating disease caused by parasitic flatworms of the genus Schistosoma. Praziquantel (PZQ), the current treatment of choice, is ineffective against immature worms and cannot prevent reinfection. The continued reliance on a single drug for treatment increases the risk of the development of PZQ-resistant parasites. Reports of PZQ insusceptibility lends urgency to the need for new therapeutics. Here, we report that Myxoma virus (MYXV), an oncolytic pox virus which is non-pathogenic in all mammals except leporids, infects and replicates in S. mansoni schistosomula, juveniles, and adult male and female worms. MYXV infection results in the shredding of the tegument and reduced egg production in vitro, identifying MYXV as the first viral pathogen of schistosomes. MYXV is currently in preclinical studies to manage multiple human cancers, supporting its use in human therapeutics. Our findings raise the exciting possibility that MYXV virus represents a novel and safe class of potential anthelmintic therapeutics.

"Every cell is an immune cell; contributions of non-hematopoietic cells to anti-helminth immunity".

Helminths are remarkably successful parasites that can invade various mammalian hosts and establish chronic infections that can go unnoticed for years despite causing severe tissue damage. To complete their life cycles, helminths migrate through multiple barrier sites that are densely populated by a complex array of hematopoietic and non-hematopoietic cells. While it is clear that type 2 cytokine responses elicited by immune cells promote worm clearance and tissue healing, the actions of non-hematopoietic cells are increasingly recognized as initiators, effectors and regulators of anti-helminth immunity. This review will highlight the collective actions of specialized epithelial cells, stromal niches, stem, muscle and neuroendocrine cells as well as peripheral neurons in the detection and elimination of helminths at mucosal sites. Studies dissecting the interactions between immune and non-hematopoietic cells will truly provide a better understanding of the mechanisms that ensure homeostasis in the context of helminth infections.

Schistosoma mansoni infection induces plasmablast and plasma cell death in the bone marrow and accelerates the decline of host vaccine responses.

Schistosomiasis is a potentially lethal parasitic disease that profoundly impacts systemic immune function in chronically infected hosts through mechanisms that remain unknown. Given the immunoregulatory dysregulation experienced in infected individuals, this study examined the impact of chronic schistosomiasis on the sustainability of vaccine-induced immunity in both children living in endemic areas and experimental infections in mice. Data show that chronic Schistosoma mansoni infection impaired the persistence of vaccine specific antibody responses in poliovirus-vaccinated humans and mice. Mechanistically, schistosomiasis primarily fostered plasmablast and plasma cell death in the bone marrow and removal of parasites following praziquantel treatment reversed the observed cell death and partially restored vaccine-induced memory responses associated with increased serum anti-polio antibody responses. Our findings strongly suggest a previously unrecognized mechanism to explain how chronic schistosomiasis interferes with an otherwise effective vaccine regimen and further advocates for therapeutic intervention strategies that reduce schistosomiasis burden in endemic areas prior to vaccination.

Schistosome TRPML channels play a role in neuromuscular activity and tegumental integrity.

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma. Mono-therapeutic treatment of this disease with the drug praziquantel, presents challenges such as inactivity against immature worms and inability to prevent reinfection. Importantly, ion channels are important targets for many current anthelmintics. Transient receptor potential (TRP) channels are important mediators of sensory signals with marked effects on cellular functions and signaling pathways. TRPML channels are a class of Ca2+-permeable TRP channels expressed on endolysosomal membranes. They regulate lysosomal function and trafficking, among other functions. Schistosoma mansoni is predicted to have a single TRPML gene (SmTRPML) with two splice variants differing by 12 amino acids. This study focuses on exploring the physiological properties of SmTRPML channels to better understand their role in schistosomes. In mammalian cells expressing SmTRPML, TRPML activators elicit a rise in intracellular Ca2+. In these cells, SmTRPML localizes both to lysosomes and the plasma membrane. These same TRPML activators elicit an increase in adult worm motility that is dependent on SmTRPML expression, indicating a role for these channels in parasite neuromuscular activity. Suppression of SmTRPML in adult worms, or exposure of adult worms to TRPML inhibitors, results in tegumental vacuolations, balloon-like surface exudates, and membrane blebbing, similar to that found following TRPML loss in other organisms. Together, these findings indicate that SmTRPML may regulate the function of the schistosome endolysosomal system. Further, the role of SmTRPML in neuromuscular activity and in parasite tegumental integrity establishes this channel as a candidate anti-schistosome drug target.

Trefoil Factor Family: A Troika for Lung Repair and Regeneration.

Tissue damage in the upper and lower airways caused by mechanical abrasion, noxious chemicals, or pathogenic organisms must be followed by rapid restorative processes; otherwise, persistent immunopathology and disease may ensue. This review will discuss evidence for the important role served by trefoil factor (TFF) family members in healthy and diseased airways of humans and rodents. Collectively, these peptides serve to both maintain and restore homeostasis through their regulation of the mucous layer and their control of cell motility, cell differentiation, and immune function in the upper and lower airways. We will also discuss important differences in which trefoil member tracks with homeostasis and disease between humans and mice, which poses a challenge for research in this area. Moreover, we discuss new evidence supporting newly identified receptor binding partners in the leucine-rich repeat and immunoglobulin-like domain-containing NoGo (LINGO) family in mediating the biological effects of TFF proteins in mouse models of epithelial repair and infection. Recent advances in our knowledge regarding TFF peptides suggest that they may be reasonable therapeutic targets in the treatment of upper and lower airway diseases of diverse etiologies. Further work understanding their role in airway homeostasis, repair, and inflammation will benefit from these newly uncovered receptor-ligand interactions.

Parasitic helminth infections in humans modulate Trefoil Factor levels in a manner dependent on the species of parasite and age of the host.

Helminth infections, including hookworms and Schistosomes, can cause severe disability and death. Infection management and control would benefit from identification of biomarkers for early detection and prognosis. While animal models suggest that Trefoil Factor Family proteins (TFF2 and TFF3) and interleukin-33 (IL-33) -driven type 2 immune responses are critical mediators of tissue repair and worm clearance in the context of hookworm infection, very little is known about how they are modulated in the context of human helminth infection. We measured TFF2, TFF3, and IL-33 levels in serum from patients in Brazil infected with Hookworm and/or Schistosomes, and compared them to endemic and non-endemic controls. TFF2 was specifically elevated by Hookworm infection in females, not Schistosoma or co-infection. This elevation was correlated with age, but not worm burden. TFF3 was elevated by Schistosoma infection and found to be generally higher in females. IL-33 was not significantly altered by infection. To determine if this might apply more broadly to other species or regions, we measured TFFs and cytokine levels (IFNγ, TNFα, IL-33, IL-13, IL-1ß, IL-17A, IL-22, and IL-10) in both the serum and urine of Nigerian school children infected with S. haematobium. We found that serum levels of TFF2 and 3 were reduced by infection, likely in an age dependent manner. In the serum, only IL-10 and IL-13 were significantly increased, while in urine IFN-γ, TNF-α, IL-13, IL-1ß, IL-22, and IL-10 were significantly increased in by infection. Taken together, these data support a role for TFF proteins in human helminth infection.

Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae.

OBJECTIVE: The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown. METHODS: WT, IL-4Rα-deficient (IL-4Rα-/-) and STAT6-deficient mice (STAT6-/-) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting. RESULTS: We show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways. CONCLUSION: Our findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.

Tuft cells in the pathogenesis of chronic rhinosinusitis with nasal polyps and asthma.

OBJECTIVE: To review the latest discoveries regarding the role of tuft cells in the pathogenesis of chronic rhinosinusitis (CRS) with nasal polyposis and asthma. DATA SOURCES: Reviews and primary research manuscripts were identified from PubMed, Google, and bioRxiv using the search words airway epithelium, nasal polyposis, CRS or asthma and chemoreceptor cell, solitary chemosensory cell, brush cell, microvillus cell, and tuft cell. STUDY SELECTIONS: Studies were selected on the basis of novelty and likely relevance to the functions of tuft cells in chronic inflammatory diseases in the upper and lower airways. RESULTS: Tuft cells coordinate a variety of immune responses throughout the body. After the activation of bitter-taste receptors, tuft cells coordinate the secretion of antimicrobial products by adjacent epithelial cells and initiate the calcium-dependent release of acetylcholine resulting in neurogenic inflammation, including mast cell degranulation and plasma extravasation. Tuft cells are also the dominant source of interleukin-25 and a significant source of cysteinyl leukotrienes that play a role in initiating inflammatory processes in the airway. Tuft cells have also been found to seem de novo in the distal airway after a viral infection, implicating these cells in dysplastic remodeling in the distal lung in the pathogenesis of asthma. CONCLUSION: Tuft cells bridge innate and adaptive immunes responses and play an upstream role in initiating type 2 inflammation in the upper and possibly the lower airway. The role of tuft cells in respiratory pathophysiology must be further investigated, because tuft cells are putative high-value therapeutic targets for novel therapeutics in CRS with nasal polyps and asthma.

Myeloid-Derived IL-33 Limits the Severity of Dextran Sulfate Sodium-Induced Colitis.

IL-33 is an IL-1 family cytokine that signals through its cognate receptor, ST2, to regulate inflammation. Whether IL-33 serves a pathogenic or protective role during inflammatory bowel disease is controversial. Herein, two different strains of cell-specific conditionally deficient mice were used to compare the role of myeloid- versus intestinal epithelial cell-derived IL-33 during dextran sodium sulfate-induced colitis. Data show that loss of CD11c-restricted IL-33 exacerbated tissue pathology, coinciding with increased tissue Il6 levels and loss of intestinal forkhead box p3+ regulatory T cells. Surprisingly, the lack of intestinal epithelial cell-derived IL-33 had no impact on disease severity or tissue recovery. Thus, we show that myeloid-derived IL-33 functionally restrains colitic disease, whereas intestinal epithelial cell-derived IL-33 is dispensable.

Cellular context of IL-33 expression dictates impact on anti-helminth immunity.

Interleukin-33 (IL-33) is a pleiotropic cytokine that can promote type 2 inflammation but also drives immunoregulation through Foxp3+Treg expansion. How IL-33 is exported from cells to serve this dual role in immunosuppression and inflammation remains unclear. Here, we demonstrate that the biological consequences of IL-33 activity are dictated by its cellular source. Whereas IL-33 derived from epithelial cells stimulates group 2 innate lymphoid cell (ILC2)-driven type 2 immunity and parasite clearance, we report that IL-33 derived from myeloid antigen-presenting cells (APCs) suppresses host-protective inflammatory responses. Conditional deletion of IL-33 in CD11c-expressing cells resulted in lowered numbers of intestinal Foxp3+Treg cells that express the transcription factor GATA3 and the IL-33 receptor ST2, causing elevated IL-5 and IL-13 production and accelerated anti-helminth immunity. We demonstrate that cell-intrinsic IL-33 promoted mouse dendritic cells (DCs) to express the pore-forming protein perforin-2, which may function as a conduit on the plasma membrane facilitating IL-33 export. Lack of perforin-2 in DCs blocked the proliferative expansion of the ST2+Foxp3+Treg subset. We propose that perforin-2 can provide a plasma membrane conduit in DCs that promotes the export of IL-33, contributing to mucosal immunoregulation under steady-state and infectious conditions.

TFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths.

Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion. Goblet cells are a specialized cell type of IEC that secrete Trefoil factor 3 (TFF3) to regulate mucus viscosity and wound healing, but whether TFF3-responsiveness requires a receptor is unclear. Here, we show that leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) is essential for TFF3-mediated functions. LINGO2 immunoprecipitates with TFF3, co-localizes with TFF3 on the cell membrane of IEC, and allows TFF3 to block apoptosis. We further show that TFF3-LINGO2 interactions disrupt EGFR-LINGO2 complexes resulting in enhanced EGFR signaling. Excessive basal EGFR activation in Lingo2 deficient mice increases disease severity during colitis and augments immunity against helminth infection. Conversely, TFF3 deficiency reduces helminth immunity. Thus, TFF3-LINGO2 interactions de-repress inhibitory LINGO2-EGFR complexes, allowing TFF3 to drive wound healing and immunity.

Cell-Intrinsic Wnt4 Influences Conventional Dendritic Cell Fate Determination to Suppress Type 2 Immunity.

Whether conventional dendritic cells (cDC) acquire subset identity under direction of Wnt family glycoproteins is unknown. We demonstrate that Wnt4, a ß-catenin-independent Wnt ligand, is produced by both hematopoietic and nonhematopoietic cells and is both necessary and sufficient for preconventional DC1/cDC1 maintenance. Whereas bone marrow cDC precursors undergo phosphoJNK/c-Jun activation upon Wnt4 treatment, loss of cDC Wnt4 in CD11cCreWnt4flox/flox mice impaired differentiation of CD24+, Clec9A+, CD103+ cDC1 compared with CD11cCre controls. Conversely, single-cell RNA sequencing analysis of bone marrow revealed a 2-fold increase in cDC2 gene signature genes, and flow cytometry demonstrated increased numbers of SIRP-α+ cDC2 amid lack of Wnt4. Increased cDC2 numbers due to CD11c-restricted Wnt4 deficiency increased IL-5 production, group 2 innate lymphoid cell expansion, and host resistance to the hookworm parasite Nippostrongylus brasiliensis Collectively, these data uncover a novel and unexpected role for Wnt4 in cDC subset differentiation and type 2 immunity.

Group 2 Innate Lymphoid Cells (ILC2): Type 2 Immunity and Helminth Immunity.

Group 2 innate lymphoid cells (ILC2) have emerged as a major component of type 2 inflammation in mice and humans. ILC2 secrete large amounts of interleukins 5 and 13, which are largely responsible for host protective immunity against helminth parasites because these cytokines induce profound changes in host physiology that include: goblet cell metaplasia, mucus accumulation, smooth muscle hypercontractility, eosinophil and mast cell recruitment, and alternative macrophage activation (M2). This review covers the initial recognition of ILC2 as a distinct cell lineage, the key studies that established their biological importance, particularly in helminth infection, and the new directions that are likely to be the focus of emerging work that further explores this unique cell population in the context of health and disease.

Development of solitary chemosensory cells in the distal lung after severe influenza injury.

H1N1 influenza virus infection induces dramatic and permanent alveolar remodeling mediated by p63+ progenitor cell expansion in both mice and some patients with acute respiratory distress syndrome. This persistent lung epithelial dysplasia is accompanied by chronic inflammation, but the driver(s) of this pathology are unknown. This work identified de novo appearance of solitary chemosensory cells (SCCs), as defined by the tuft cell marker doublecortin-like kinase 1, in post-influenza lungs, arising in close proximity with the dysplastic epithelium, whereas uninjured lungs are devoid of SCCs. Interestingly, fate mapping demonstrated that these cells are derived from p63-expressing lineage-negative progenitors, the same cell of origin as the dysplastic epithelium. Direct activation of SCCs with denatonium + succinate increased plasma extravasation specifically in post-influenza virus-injured lungs. Thus we demonstrate the previously unrecognized development and activity of SCCs in the lung following influenza virus infection, implicating SCCs as a central feature of dysplastic remodeling.

Fungal extracts stimulate solitary chemosensory cell expansion in noninvasive fungal rhinosinusitis.

BACKGROUND: Solitary chemosensory cells (SCCs) are rare epithelial cells enriched in nasal polyps and are the primary source of interleukin-25 (IL-25), an innate cytokine eliciting T-helper 2 (Th2) immune response. Although it is proposed that SCCs are stimulated by antigens released by upper airway pathogens, the exogenous triggers of human SCCs remain elusive. We studied patients with noninvasive fungal rhinosinusitis to determine whether extracts of Aspergillus fumigatus and Alternaria alternata stimulate SCC proliferation as an early event in type 2 inflammation. METHODS: Multicolor flow cytometry, immunofluorescence, and enzyme-linked immunoassay were used to interrogate mucosa from patients with mycetomas and allergic fungal rhinosinusitis (AFRS) for SCCs and IL-25. Primary sinonasal epithelial cells from AFRS patients and noninflamed inferior turbinates were stimulated with fungal extracts for 72 hours, and SCC population frequency as well as mitotic activity were quantified using flow cytometry. RESULTS: SCCs producing IL-25 are enriched in inflamed mucosa compared with intrapatient noninflamed control tissue (38.6% vs 6.5%, p = 0.029). In cultured sinonasal epithelial cells from AFRS nasal polyps, Aspergillus fumigatus and Alternaria alternata stimulated higher SCC frequency compared with controls (27.4% vs 10.6%, p = 0.002; 18.1% vs 10.6%, p = 0.046), which led to increased IL-25 secretion in culture media (75.5 vs 3.3 pg/mL, p < 0.001; 32.3 vs 3.3 pg/mL, p = 0.007). Ki-67 expression was higher in SCCs grown in fungal stimulation conditions compared with controls. CONCLUSION: Although fungal antigens are known to potentiate immune response through innate cytokines, including IL-25, the early expansion of SCCs in the presence of fungus has not been described. This early event in the pathogenesis of noninvasive fungal rhinosinusitis may represent a target for intervention.

Macrophages promote epithelial proliferation following infectious and non-infectious lung injury through a Trefoil factor 2-dependent mechanism.

Coordinated efforts between macrophages and epithelia are considered essential for wound healing, but the macrophage-derived molecules responsible for repair are poorly defined. This work demonstrates that lung macrophages rely upon Trefoil factor 2 to promote epithelial proliferation following damage caused by sterile wounding, Nippostrongylus brasiliensis or Bleomycin sulfate. Unexpectedly, the presence of T, B, or ILC populations was not essential for macrophage-driven repair. Instead, conditional deletion of TFF2 in myeloid-restricted CD11cCre TFF2 flox mice exacerbated lung pathology and reduced the proliferative expansion of CD45- EpCAM+ pro-SPC+ alveolar type 2 cells. TFF2 deficient macrophages had reduced expression of the Wnt genes Wnt4 and Wnt16 and reconstitution of hookworm-infected CD11cCre TFF2flox mice with rWnt4 and rWnt16 restored the proliferative defect in lung epithelia post-injury. These data reveal a previously unrecognized mechanism wherein lung myeloid phagocytes utilize a TFF2/Wnt axis as a mechanism that drives epithelial proliferation following lung injury.

Solitary chemosensory cells are a primary epithelial source of IL-25 in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: IL-25 can function as an early signal for the respiratory type 2 response characteristic of allergic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). In the mouse gut, tuft cells are the epithelial source of IL-25. However, the source of human airway epithelial IL-25 has remained elusive. OBJECTIVE: In this study we sought to determine whether the solitary chemosensory cell (SCC) is the predominant source of IL-25 in the sinonasal epithelium. METHOD: Flow cytometry and immunofluorescence for SCCs and IL-25 were used to interrogate polyp and turbinate tissue from patients with CRSwNP. Mucus was collected during acute inflammatory exacerbations from patients with CRSwNP or chronic rhinosinusitis without nasal polyps and IL-25 levels determined by using ELISA. Lastly, sinonasal epithelial cultures derived from polyp and turbinate tissue were stimulated with IL-13 and analyzed for SCC proliferation and IL-25 production. RESULTS: This study demonstrates that a discrete cell type, likely an SCC, characterized by expression of the taste-associated G protein gustducin and the intestinal tuft cell marker doublecortin-like kinase 1, is the predominant source of IL-25 in the human upper airway. Additionally, we show that patients with CRSwNP have increased numbers of SCCs in nasal polyp tissue and that in vitro IL-13 exposure both increased proliferation and induced apical secretion of IL-25 into the mucosal layer. CONCLUSIONS: Inflammatory sinus polyps but not adjacent turbinate tissue show expansion of the SCC population, which is the source of epithelial IL-25.

Solitary chemosensory cells producing interleukin-25 and group-2 innate lymphoid cells are enriched in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is commonly characterized by type-2 inflammation. It is established that group-2 innate lymphoid cells (ILC2s) are a subset of immune cells important in orchestrating mucosal type-2 response. IL-25 is an epithelial-derived cytokine that is a critical activator of ILC2s. Recent evidence demonstrates that specialized taster epithelial cells, such as solitary chemosensory cells (SCCs), may be producers of IL-25. To elucidate the relationship between SCCs and ILC2s in CRSwNP, we sought to quantify ILC2s and SCCs to determine if these cell types are enriched in nasal polyps compared to healthy sinonasal mucosa. METHODS: We quantified SCCs and ILC2s using multicolor flow cytometry in nasal polyps and non-inflamed turbinate mucosa from seven patients and investigated the role of IL-13 and dexamethasone on SCC frequency using tissue explants of nasal polyps and turbinate mucosa. RESULTS: SCCs were found to be the primary source of IL-25. Nasal polyps demonstrated higher populations of SCCs (33.0% vs 5.6%, p < 0.001) and ILC2s (2.40% vs 0.19%, p = 0.008) compared to patient-matched nonpolypoid turbinates. In cultured polyp explants, exogenous IL-13 increased the proportion of epithelial SCCs (40.2% IL-13 condition vs 28.9% untreated, p = 0.012), and this effect was reversed by addition of dexamethasone (40.2% vs 8.9%, p < 0.0005). CONCLUSION: These data support SCC and ILC2 expansion as well as increased IL-25 production in nasal polyps and may represent early events in the pathogenesis of CRSwNP. IL-13 stimulates proliferation of SCC in a feed-forward loop, a process that is steroid-sensitive.