IL-33 priming and antigenic stimulation synergistically promote the transcription of proinflammatory cytokine and chemokine genes in human skin mast cells

Abstract

Background Antigenic stimulation through cross-linking the IgE receptor and epithelial cell-derived cytokine IL-33 are potent stimuli of mast cell (MC) activation. Moreover, IL-33 primes a variety of cell types, including MCs to respond more vigorously to external stimuli. However, target genes induced by the combined IL-33 priming and antigenic stimulation have not been investigated in human skin mast cells (HSMCs) in a genome-wide manner. Furthermore, epigenetic changes induced by the combined IL-33 priming and antigenic stimulation have not been evaluated. Results We found that IL-33 priming of HSMCs enhanced their capacity to promote transcriptional synergy of the IL1B and CXCL8 genes by 16- and 3-fold, respectively, in response to combined IL-33 and antigen stimulation compared to without IL-33 priming. We identified the target genes in IL-33-primed HSMCs in response to the combined IL-33 and antigenic stimulation using RNA sequencing (RNA-seq). We found that the majority of genes synergistically upregulated in the IL-33-primed HSMCs in response to the combined IL-33 and antigenic stimulation were predominantly proinflammatory cytokine and chemokine genes. Moreover, the combined IL-33 priming and antigenic stimulation increase chromatin accessibility in the synergy target genes but not synergistically. Transcription factor binding motif analysis revealed more binding sites for NF-κB, AP-1, GABPA, and RAP1 in the induced or increased chromatin accessible regions of the synergy target genes. Conclusions Our study demonstrates that IL-33 priming greatly potentiates MCs’ ability to transcribe proinflammatory cytokine and chemokine genes in response to antigenic stimulation, shining light on how epithelial cell-derived cytokine IL-33 can cause exacerbation of skin MC-mediated allergic inflammation.

Crosstalk between Regnase-1 and -3 shapes mast cell survival and cytokine expression

“…Analysis of the expression of Zc3h12a-d in mast cells extracted ex vivo from different mouse tissues (ImmGen database) ( Dwyer et al, 2016 ) also revealed the high expression of Zc3h12c in most tissue-derived mast cells (notably from the skin, less prominently from the peritoneal cavity), followed by the modest expression of Zc3h12a and very low levels of Zc3h12b and Zc3h12d ( Fig S1D ). Finally, data mining of published RNA-seq data from human mast cells revealed induction of ZC3H12A and ZC3H12C expression in stimulated mast cells obtained from the human skin ( Gao et al, 2023 ). Similar results were obtained by RNA-seq of stimulated human peripheral blood–derived mast cells ( Cildir et al, 2019 ) ( Fig S1E ).…”

“…(D) Expression of Regnase genes ( Zc3h12a-d ) in mast cells isolated from different mouse tissues, from Dwyer et al (2016) . (E) RNA-seq data of human mast cells obtained from the skin (left panel) ( Gao et al, 2023 ) and CD34 + precursor–derived human mast cells (right panel) ( Cildir et al, 2019 ), showing induction of both ZC3H12A and ZC3H12C expression, as well as the expected induction of cytokines. (F, G) Schematic diagrams of murine mast cell (F) in vitro differentiation from bone marrow and (G) ex vivo isolation, enrichment, and in vitro expansion from mouse peritoneum.…”

CREB Is Indispensable to KIT Function in Human Skin Mast Cells—A Positive Feedback Loop between CREB and KIT Orchestrates Skin Mast Cell Fate

“…In the skin micro-milieu, SCF is expressed by structural cells, such as keratinocytes [ 81 , 82 ], endothelial cells [ 83 , 84 ], fibroblasts [ 85 , 86 ], and dermal papilla cells [ 17 , 87 ]. MCs can be isolated from the lung, gut, and skin and, at high concentrations, SCF prompts these mature MCs to re-enter the cell cycle [ 54 , 60 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. The modifications elicited by SCF in skin MCs are accompanied by massive changes in the phosphoproteome, with roughly 5400 out of 10,500 phosphosites incurring changes in abundance [ 8 ].…”