IL-4–BATF signaling directly modulates IL-9 producing mucosal mast cell (MMC9) function in experimental food allergy - 09/01/21
, Simon P. Hogan, PhD a, b, c, ⁎ 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. In silico 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.
Il testo completo di questo articolo è disponibile in PDF.Graphical abstract |
Key words : Food allergy, IL-4, IL-9, mast cell, BATF, transcriptome, metabolism
Abbreviations used : APC, BM, CCHMC, DEG, GFP, ILC2, Lin, LP, MC, MCPT-1, MMC9, MMC9-L, OVA, qPCR, RPKM, SCF, scRNA-seq, SI, SSC, UMAP, WT
Mappa
| This work was supported by grants DK073553, AI112626, AI138177, AI140133, and DoD W81XWH-15-1-051730 from the National Institutes of Health (to Y.-H.W. and S.P.H.); and by the Food Allergy Research and Education, M-FARA, and Mary H. Weiser Food Allergy Center (to S.P.H). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 1
P. 280-295 - Gennaio 2021 Ritorno al numero
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