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

Kohanski, Michael A.; Workman, Alan D.; Patel, Neil N.; Hung, Li-Yin; Shtraks, Julie P.; Chen, Bei; Blasetti, Mariel; Doghramji, Laurel; Kennedy, David W.; Adappa, Nithin D.; Palmer, James N.; Herbert, De’Broski R.; Cohen, Noam A.

doi:10.1016/j.jaci.2018.03.019

Cited by 126 publications

(127 citation statements)

References 41 publications

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“…65 Recently, Kohanski et al demonstrated that SCCs are the primary epithelial source of IL-25 in the sinonasal epithelium. 19 Furthermore, similar to murine models, data support that humans have a similar feed-forward loop in which IL-25 from SCCs activate downstream IL-13, that then drives SCC expansion and further enhances IL-25 production 23 (Figure 1). …”

Section: Novel Cell Types Involved In Epithelial-mediated Type-2 Inflmentioning

confidence: 62%

“…17,18 More recently, a specialized group of epithelial cells called solitary chemosensory cells were found to be the major epithelial source of IL-25 in the human upper airway. 19 The receptor for IL-25 is a heterodimer comprised of IL-17RA and IL-17RB. Each component of the receptor is necessary for IL-25 function, as mice that were null for either subunit were not able to mount a type-2 response.…”

Section: Cellular Sources and Function Of Tslp Il-25 And Il-33mentioning

confidence: 99%

“…23 Moreover, IL-13 produced by activated ILC2s has been found to be acting in a feed-forward loop to further propagate IL-25 production. 19,23 …”

Section: Cellular Sources and Function Of Tslp Il-25 And Il-33mentioning

confidence: 99%

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Sentinels at the wall: epithelial‐derived cytokines serve as triggers of upper airway type 2 inflammation

Patel

Kohanski

Maina

et al. 2018

Int Forum Allergy Rhinol

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Recent evidence has demonstrated an expanding role of respiratory epithelial cells in immune surveillance and modulation. Studies have been focusing on the earliest events that link epithelial injury to downstream inflammatory responses. Cytokines produced by and released from respiratory epithelial cells are among these early trigger signals. Epithelial-derived cytokines, namely thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33, have come to the forefront of recent investigations. Each of these 3 cytokines has been implicated in chronic rhinosinusitis (CRS), asthma, and atopy. Herein we review studies elucidating the roles of epithelial-derived cytokines in the pathobiology of upper airway disease, with particular emphasis on type 2 inflammatory conditions.

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Section: Novel Cell Types Involved In Epithelial-mediated Type-2 Inflmentioning

confidence: 62%

Section: Cellular Sources and Function Of Tslp Il-25 And Il-33mentioning

confidence: 99%

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Sentinels at the wall: epithelial‐derived cytokines serve as triggers of upper airway type 2 inflammation

Patel

Kohanski

Maina

et al. 2018

Int Forum Allergy Rhinol

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“…37 IL-25 is produced by inflamed airway epithelial cells, 3,35 eosinophils, 38 tuft cells in the intestinal and respiratory tracts, [39][40][41] and solitary chemosensory cells in the airways. 42 IL-25, in combination with neuropeptides, such as neuromedin U, which is released from sensory neurons in the lungs, and calcitonin gene-related peptide, which is released from pulmonary neuroendocrine cells, can promote type 2 immunity in allergen-driven AHR 1,2,43-45 by enhancing production of IL-4, IL-5, and IL-13 from ILC2s, T H 2 cells, and RGMb 1 interstitial macrophages. 2,23,[44][45][46] Although RGMb 1 interstitial macrophages in saline-treated control mice express only low levels of IL-17RB, we found that after either OVA or CRA sensitization and challenge, RGMb 1 interstitial macrophages were the most numerous IL-17RB-expressing cells, accounting for about 98% of IL-17RB 1 cells in the lung.…”

Section: Discussionmentioning

confidence: 99%

Blockade of RGMb inhibits allergen-induced airways disease

Leung

Kim

et al. 2019

Journal of Allergy and Clinical Immunology

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Background: Allergic asthma causes morbidity in many subjects, and novel precision-directed treatments would be valuable. Objective: We sought to examine the role of a novel innate molecule, repulsive guidance molecule b (RGMb), in murine models of allergic asthma. Methods: In models of allergic asthma using ovalbumin or cockroach allergen, mice were treated with anti-RGMb or control mAb and examined for airway inflammation and airway hyperreactivity (AHR), a cardinal feature of asthma. The mechanisms by which RGMb causes airways disease were also examined. Results: We found that blockade of RGMb by treatment with anti-RGMb mAb effectively blocked the development of airway inflammation and AHR. Importantly, blockade of RGMb completely blocked the development of airway inflammation and AHR, even if treatment occurred only during the challenge (effector) phase. IL-25 played an important role in these models of asthma because IL-25 receptor-deficient mice did not develop disease after sensitization and challenge with allergen. RGMb was expressed primarily by innate cells in the lungs, including bronchial epithelial cells (known producers of IL-25), activated eosinophils, and interstitial macrophages, which in the inflamed lung expressed the IL-25 receptor and produced IL-5 and IL-13. We also found that neogenin, the canonical receptor for RGMb, was expressed by interstitial macrophages and bronchial epithelial cells in the inflamed lung, suggesting that an innate RGMb-neogenin axis might modulate allergic asthma. Conclusions: These results demonstrate an important role for a novel innate pathway in regulating type 2 inflammation in patients with allergic asthma involving RGMb and RGMbexpressing cells, such as interstitial macrophages and bronchial epithelial cells. Moreover, targeting this previously unappreciated innate pathway might provide an important treatment option for allergic asthma. (J Allergy Clin Immunol 2019;144:94-108.)

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“…Recent studies by our group revealed that rare chemosensing epithelial cells, called solitary chemosensory cells (SCCs), are elevated in patients who have chronic rhinosinusitis with nasal polyposis (CRSwNP) . Moreover, SCCs were found to be the primary source of interleukin‐25 (IL‐25), an important innate cytokine that elicits a downstream type 2 inflammatory response . Although it is known that solitary chemosensory cells can detect substances in the mucosal environment, the exact link between pathogens and detected antigenic substances remains elusive.…”

mentioning

confidence: 99%

Fungal extracts stimulate solitary chemosensory cell expansion in noninvasive fungal rhinosinusitis

Patel

Triantafillou

Maina

et al. 2019

Int Forum Allergy Rhinol

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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. C 2019 ARS-AAOA, LLC.

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

Abstract: Inflammatory sinus polyps but not adjacent turbinate tissue show expansion of the SCC population, which is the source of epithelial IL-25.

Cited by 126 publications

References 41 publications

Sentinels at the wall: epithelial‐derived cytokines serve as triggers of upper airway type 2 inflammation

Sentinels at the wall: epithelial‐derived cytokines serve as triggers of upper airway type 2 inflammation

Blockade of RGMb inhibits allergen-induced airways disease

Fungal extracts stimulate solitary chemosensory cell expansion in noninvasive fungal rhinosinusitis

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