Understanding the Influence of IL4 Priming on IL33 Stimulated Cord Blood Mast Cells

Hannah Martin, MD
Department of Medicine
Division of Rheumatology, Immunology, and Allergy
Poster Overview

Mast cells are immune cells that release substances, such as histamine, that lead to allergic reactions, such as hives, swelling, shortness of breath, and low blood pressure. Mast cells can be activated by different signals in the body. Our goal was to see how these signals interact and change mast cell responses at the level of the RNA. The two signals specifically looked at were IL4, which is a signal that is seen in allergic diseases, and IL33, a danger signal released during allergy exposure or damage to different cells, such as skin cells. We stimulated mast cells grown from human umbillical cord blood with IL4 and IL33 and looked at how both signals changed RNA transcript responses within MCs. The two signals together lead to mast cell upregulation of other allergy-associagted signals, specifically IL5 and IL13, but decreased expression of other signals associated with NKFB, indicating that IL4 “rewires” the mast cell, fundamentally changing how it responds to IL33.

Scientific Abstract

Rationale: Mast cells (MCs) are tissue resident immune effector cells that are activated through innate danger signals, including the epithelial-derived cytokine IL-33, and adaptive IgE-mediated responses. Previous studies have shown that the cytokine IL4 enhances human umbilical cord blood-derived MCs (CBMC) to IgE and lipid signals PGE2 and leukotriene C4. We explore how IL4 modifies MC responses to IL33 using RNA sequencing (RNAseq).

Methods: CBMCs were stimulated with IL4 (IL4-primed) or vehicle (unprimed) for 72 hours. IL4- primed and unprimed CBMCs were stimulated with IL33 and compared to unstimulated CBMCs using RNAseq.

Results: IL4 priming lead to significant upregulation of 158 genes, while 147 genes were significantly downregulated. IL33-elicited transcripts enhanced by IL4 priming included BCL2L1, a prominent target of the mTOR pathway, and genes encoding TH2 inflammation-associated cytokines, IL5 and IL13, while IL1B, TNF, and NKFBIA were downregulated.

Conclusions: The majority of IL33-elicited transcripts were unchanged by IL4 priming, suggesting that IL4 modifies MC responses to innate signals by targeting specific pathways. The mTOR pathway, associated with IL5, IL13, and BCL2L1, seems to be enhanced by IL4, while IL1B and TNF, associated with NKFB signaling, is downregulated. IL4 priming shifts the mast cell response to a more TH2 driven response.

Clinical Implications
Clinical Implications: Understanding how different signals change the mast cell helps us understand if ultimately there are aspects of mast cell signaling that we can block or alter that can improve allergic diseases.
Research Areas
Hannah Martin, MD, Chunli Feng, MD, Joshua A. Boyce, MD, Daniel F. Dwyer, PhD
Principal Investigator

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