Abstract Description Viral infections are the primary trigger for exacerbating allergic inflammation. During infections, injured epithelial cells release IL-33 to act on mast cells (MCs). Although IL-33 primes various cell types to respond more vigorously to external stimuli, it has not been investigated at the genome-wide level whether it enhances MCs’ responses to antigenic stimulation. In this study, we primed primary human skin MCs (HSMCs) and bone marrow MCs (BMMCs) with IL-33 and then stimulated them with antigenic stimulation via IgE receptor crosslinking. We found that IL-33 priming greatly potentiates MCs’ ability to transcribe several categories of genes, including genes encoding proinflammatory cytokine and chemokine, signaling molecules, molecules involved in cell survival and cell death, and transcription factors. Examples of these genes include CXCL8, Il13, BCL2A1, BCL6, SKIL, TWIST2 in HSMCs and Ccl1, Il13, Tnfrsf9, Pdcd1lg2, Nfkbiz, and Pou2f2 in BMMCs. Furthermore, we performed ATAC-seq analysis to investigate whether the combined stimulations synergistically affect chromatin accessibility. Although the combined stimulations moderately increased chromatin accessibility, these increases do not fully explain how IL-33 and antigenic stimulation synergistically upregulate their target genes. Our study demonstrates that IL-33 potentiates MCs to respond to antigenic stimulation, implying a novel mechanism by which IL-33 can cause exacerbation of MC-mediated allergic inflammation. Funding Sources Supported by grants from the National Institutes of Health R01AI107022 and R01AI135194 (H.H.), National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) Pilot Project P20GM103641 (C.A.O. and G.G.), a fund provided by a fellowship from the Higher Committee for Education Development and Ministry of Higher Education and Scientific Research in Iraq (Z.M.). Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)
Junfeng Gao (Sat,) studied this question.