Mina Derakhshan, PhD

Research Fellow
Rheumatology, Immunology, and Allergy
TGF-β regulation of intraepithelial mast cell phenotype and function

Principal Investigator: Daniel Dwyer

Authors: T.M. Derakhshan, E. Hollers, K. Buchheit, T. Laidlaw, J.A. Boyce, D.F. Dwyer
Lay Abstract

Mast cells (MCs) are immune cells that expand in the airway, esophagus, and intestine during allergic disease. These expanded MCs are very different from those found in healthy individuals. In mice, TGF-β is a signal produced by epithelial cells that plays a role in the development of allergy-expanded MCs within the epithelium, but the factors controlling the development of these MCs in humans are unknown. We screened the transcriptome of MCs in nasal polyps and found signals that suggest a role of TGF-β in the development of MCs, so we experimentally tested the effects TGF-β on peripheral blood-derived MCs. When MCs were stimulated with TGF-β, the expression level of transcripts associated with allergy-expanded MCs within the epithelium were increased, while in contrast, the expression of transcripts associated with MCs residing in other compartments were decreased. We then measured the expression of a few of these factors by another technique and found that the expressions at the protein level are altered by TGF-β in accordance with their anatomical locations. Therefore, our findings suggest for a role of TGF-β in expansion of MCs within epithelium during allergic inflammatory diseases.

Scientific Abstract

Mast cells (MCs) are potent immune effector cells that expand within the airway epithelium and generate proinflammatory mediators during type 2 inflammatory disease, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Intraepithelial MCs (MCTs) are phenotypically different from subepithelial ones (MCTCs), however the signaling pathways driving these phenotypes are unclear. We previously identified a role for TGF-β in directing murine intraepithelial MC development and hypothesize that TGF-β plays a similar role in humans. To test this, human peripheral blood-derived MCs (PB-MCs) were treated with TGF-β1 and analyzed through RNA-sequencing and flow cytometry. Inflammatory mediator generation was assessed following activation with innate and adaptive immune stimuli. TGF-β priming directed a transcriptional program in PB-MCs that strongly paralleled MCTs in vivo, including upregulating leukotriene-generating enzymes (ALOX5AP, LTC4S), while downregulating MCTC-associated proteases (CMA1, CTSG) and receptors (CD117, MRGPRX2). Flow cytometric evaluation confirmed that both chymase and the MRGPRX2 were strongly expressed by PB-MCs at baseline but virtually absent when the cells were grown in the presence of TGF-β. Further, TGF-β-priming dramatically altered MC release of pro-inflammatory mediators in response to activating signals. Thus, TGF-β directs a human intraepithelial MC phenotype, altering both the MC protease profile and their response to activating stimuli.

Clinical Implications
Asthma and chronic rhinosinusitis affect nearly 30 million Americans, therefore understanding the disease pathogenesis is crucial. Mast cells are key effector cells during airway inflammation and inhibiting the factors that regulate their development and functional modulations has important therapeutic implications.

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