Sensory Neurons Initiate Tuft Cell-Dependent Sinonasal Allergic Inflammation via Substance P = Las Neuronas Sensoriales Inician la Inflamacion Alergica Sinonasal Dependiente de las Celulas de Penacho a traves de la Sustancia P / Jorge Felipe Ortiz-Carpena.

Format:

Book

Thesis/Dissertation

Author/Creator:

Ortiz-Carpena, Jorge Felipe, author.

Contributor:

University of Pennsylvania. Immunology, degree granting institution.

Language:

English

Subjects (All):

Immunology.

Neurosciences.

Microbiology.

Cellular biology.

Immunology--Penn dissertations.

Penn dissertations--Immunology.

Local Subjects:

Immunology.

Neurosciences.

Microbiology.

Cellular biology.

Immunology--Penn dissertations.

Penn dissertations--Immunology.

Physical Description:

1 online resource (175 pages)

Contained In:

Dissertations Abstracts International 85-03B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.

Ann Arbor : ProQuest Dissertations & Theses, 2023

Language Note:

English

Summary:

The precise role and potential interactions of tuft cells with trigeminal sinonasal neurons in the context of allergic disease remain largely unexplored and unclear. This study investigated the impact of intranasal administration of house dust mite or fungal allergens on these cells and sought to understand the mechanisms underpinning the allergic response. We observed that these allergens incited a significant expansion in tuft cells, eosinophilia, sneezing, Type 2 immune responses, and elevated release of neuropeptides. Strikingly, mice devoid of tuft cells exhibited an absence of these responses, notwithstanding the persistence of eosinophilia and elevated neuropeptide levels. Ablation of Transient Receptor Potential Channel Vanilloid 1 (TRPV1)+ neurons prevented allergen-evoked tuft cell expansion and eosinophilia without affecting ILC2 and CD4+ TH2 cell recruitment. In addition, exposure of naive TG neurons to allergen evoked calcium influx and neuropeptide release, but only Substance P (SP) adaptively increased upon repetitive allergen exposure. We found that SP not only guided tuft cell lineage commitment, but also initiated allergic inflammation. To substantiate this, we targeted the SP receptor, neurokinin 1, through ablation or inhibition. This led to a reversal of allergen-induced sneezing, tuft cell expansion, and eosinophilia, thereby emphasizing the critical role of SP and its receptor in Type 2 immunity. Based on our findings, we put forth the hypothesis that sinonasal nociceptors detect protease-containing allergens and adaptively secrete SP. This then acts as a key driver for tuft cell expansion and the early features of Type 2 immunity. This novel understanding of the mechanistic underpinnings of allergic responses opens the door for further research and potential therapeutic interventions in allergic disease.

El papel preciso y las posibles interacciones de las celulas de penacho con las neuronas trigeminales sinonasales en el contexto de la enfermedad alergica permanecen en gran medida inexplorados e inciertos. Este estudio investigo el impacto de la administracion intranasal de acaros del polvo domestico o alergenos fungicos en estas celulas y busco entender los mecanismos que subyacen en la respuesta alergica. Observamos que estos alergenos incitaban una expansion significativa en las celulas de penacho, eosinofilia, estornudos, respuestas inmunitarias de tipo 2 y liberacion elevada de neuropeptidos. Sorprendentemente, los ratones carentes de celulas de penacho mostraron una ausencia de estas respuestas, a pesar de la persistencia de la eosinofilia y los niveles elevados de neuropeptidos. La ablacion de las neuronas Transiente Receptor Potencial Canal Vanilloid 1 (TRPV1)+ previno la expansion de las celulas de penacho y la eosinofilia inducida por alergenos sin afectar la reclutacion de celulas ILC2 y CD4+ Th2. Ademas, la exposicion de neuronas trigeminales a alergenos provoco la entrada de calcio y la liberacion de neuropeptidos, pero solo la Sustancia P (SP) aumento adaptativamente tras la exposicion repetitiva a alergenos. Encontramos que la SP no solo guiaba la diferenciacion de las celulas de penacho, sino que tambien iniciaba la inflamacion alergica. Para corroborar esto, dirigimos nuestra atencion al receptor de SP, neuroquinina 1, a traves de la ablacion o inhibicion. Esto condujo a una reversion del estornudo, la expansion de las celulas de penacho y la eosinofilia inducida por alergenos, enfatizando asi el papel critico de la SP y su receptor en la inmunidad de Tipo 2. Basandonos en nuestros hallazgos, proponemos la hipotesis de que los nociceptores sinonasales detectan alergenos que contienen proteasas y secretan adaptativamente SP. Esta entonces actua como un impulsor clave para la expansion de las celulas de penacho y las caracteristicas tempranas de la inmunidad de Tipo 2. Esta nueva comprension de los fundamentos mecanicistas de las respuestas alergicas abre la puerta a futuras investigaciones e intervenciones terapeuticas potenciales en la enfermedad alergica.

Notes:

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

Advisors: Herbert, De'Broski R.; Committee members: Henrickson, Sarah E.; Oliver, Paula M.; Lazarevic, Vanja; Cohen, Noam A.; Vaughan, Andrew E.

Department: Immunology.

Ph.D. University of Pennsylvania 2023.

Local Notes:

School code: 0175

ISBN:

9798380384476

Access Restriction:

Restricted for use by site license.

This item is not available from ProQuest Dissertations & Theses.