IL-4-BATF signaling directly modulates IL-9 producing mucosal mast cell (MMC9) function in experimental food allergy.

Abstract

BACKGROUND:

This study group has previously identified IL-9-producing mucosal mast cell (MMC9) as the primary source of IL-9 to drive intestinal mastocytosis and experimental IgE-mediated food allergy. However, the molecular mechanisms that regulate the expansion of MMC9s remain unknown.

OBJECTIVES:

This study hypothesized that IL-4 regulates MMC9 development and MMC9-dependent experimental IgE-mediated food allergy.

METHODS:

An epicutaneous sensitization model was used and bone marrow reconstitution experiments were performed to test the requirement of IL-4 receptor α (IL-4Rα) signaling on MMC9s in experimental IgE-mediated food allergy. Flow cytometric, bulk, and single-cell RNA-sequencing analyses on small intestine (SI) MMC9s were performed to illuminate MMC9 transcriptional signature and the effect of IL-4Rα signaling on MMC9 function. A bone marrow-derived MMC9 culture system was used to define IL-4-BATF signaling in MMC9 development.

RESULTS:

Epicutaneous sensitization- and bone marrow reconstitution-based models of IgE-mediated food allergy revealed an IL-4 signaling-dependent cell-intrinsic effect on SI MMC9 accumulation and food allergy severity. RNA-sequencing analysis of SI-MMC9s identified 410 gene transcripts reciprocally regulated by IL-4 signaling, including Il9 and Batf. Insilico analyses identified a 3491-gene MMC9 transcriptional signature and identified 2 transcriptionally distinct SI MMC9 populations enriched for metabolic or inflammatory programs. Employing an in vitro MMC9-culture model system showed that generation of MMC9-like cells was induced by IL-4 and this was in part dependent on BATF.

CONCLUSIONS:

IL-4Rα signaling directly modulates MMC9 function and exacerbation of experimental IgE-mediated food allergic reactions. IL-4Rα regulation of MMC9s is in part BATF-dependent and occurs via modulation of metabolic transcriptional programs.

• Authors: Sunil Tomar, Varsha Ganesan, Ankit Sharma, Chang Zeng, Lisa Waggoner, Andrew Smith, Chang H Kim, Paula Licona-Limón, Richard L Reinhardt, Richard A Flavell, Yui-Hsi Wang, Simon P Hogan
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 147 Issue 1 Pg. 280-295 (01 2021) ISSN: 1097-6825 [Electronic] United States
• PMID: 33069715 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Basic-Leucine Zipper Transcription Factors
• Batf protein, mouse
• Il4 protein, mouse
• Interleukin-9
• Interleukin-4

Topics

• Animals
• Basic-Leucine Zipper Transcription Factors (genetics, immunology)
• Disease Models, Animal
• Food Hypersensitivity (genetics, immunology, pathology)
• Interleukin-4 (genetics, immunology)
• Interleukin-9 (genetics, immunology)
• Intestinal Mucosa (immunology, pathology)
• Mast Cells (immunology, pathology)
• Mice
• Mice, Knockout
• Signal Transduction (genetics, immunology)