IL-4-BATF signaling directly modulates IL-9 producing mucosal mast cell (MMC9) function in experimental food allergy.
IL-4-BATF signaling directly modulates IL-9 producing mucosal mast cell (MMC9) function in experimental food allergy.
复制标题
IL-4-BATF信号直接调节IL-9在实验食品过敏中产生粘膜肥大细胞（MMC9）功能。
DOI：
10.1016/j.jaci.2020.08.043
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Hogan SP
中科院分区：
文献类型：
--
作者：
Tomar S;Ganesan V;Sharma A;Zeng C;Waggoner L;Smith A;Kim CH;Licona-Limón P;Reinhardt RL;Flavell RA;Wang YH;Hogan SP
We have 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. We hypothesized that IL-4 regulates MMC9 development and MMC9-dependent experimental IgE-mediated food allergy. We utilized an epicutaneous sensitization-model and performed bone marrow (BM) reconstitution experiments, to test the requirement of IL-4Rα signaling on MMC9’s in experimental IgE-mediated food allergy. Flow cytometric, bulk and single cell RNA-seq analysis on small intestine (SI)-MMC9s was performed to illuminate MMC9 transcriptional signature and the effect of IL-4Rα signaling on MMC9 function. BM-derived MMC9 culture system was used to define IL-4-BATF signaling in MMC9 development. Epicutaneous sensitization and BM reconstitution based models of IgE-mediated food allergy revealed an IL-4 signaling-dependent cell-intrinsic effect on SI-MMC9 cell accumulation and food allergy severity. RNA-seq analysis of SI-MMC9 cells identified 410 gene transcripts reciprocally regulated by IL-4 signaling, including Il9 and Basic leucine zipper ATF-like transcription factor (Batf). In silico analyses identified a 3491-gene MMC9 transcriptional signature and identified two transcriptionally distinct SI-MMC9 populations enriched for metabolic or inflammatory programs. Employing an in vitro MMC9-culture model system we show that generation of MMC9-like cells was induced by IL-4 and this was in part dependent on BATF. 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 via modulation of metabolic transcriptional programs. IL-4R/BATF-signaling mechanism regulates IL-9 producing mucosal mast cell transcriptional programs and induction of experimental IgE-mediated food allergy.
