Immunology

Real-time imaging of asthmatic epithelial cells identifies migratory deficiencies under Type-2 conditions



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Abstract

Background

The epithelium is increasingly recognized as a pathologic contributor to asthma and
its phenotypes. Although delayed wound closure by asthmatic epithelial cells is consistently
observed, underlying mechanisms remain poorly understood, partly due to difficulties
in studying dynamic physiologic processes involving polarized multilayered cell systems.
Although Type-2 immunity has been suggested to play a role, the mechanisms by which
repair is diminished are unclear.

Objective

To develop and utilize primary multilayered polarized epithelial cell systems, derived
from asthmatic patients, to evaluate cell migration in response to wounding under
Type-2 and untreated conditions.

Methods

A novel wounding device for multilayered polarized cells, along with time-lapse live
cell/real-time confocal imaging were evaluated under IL-13 and untreated conditions.
The influence of inhibition of the Type-2 enzyme, 15 lipoxygenase (15LO1), on the
process was also addressed. Cell migration patterns were analyzed by high dimensional
Frequency Modulated Möbius for statistical comparisons.

Results

IL-13 stimulation negatively impacts wound healing by altering the Total speed, directionality
and acceleration of individual cells. Inhibition 15LO1 partially improved the wound
repair through improving Total speed.

Conclusions

Migration abnormalities contributed to markedly slower wound closure of IL-13 treated
cells, which was modestly reversed by 15LO1 inhibition, suggesting its potential as
an asthma therapeutic target. These novel methodologies offer new ways to dynamically
study cell movements and identify contributing pathologic processes.

Article Info

Publication History

Publication stage

In Press Journal Pre-Proof

Footnotes

Conflicts of Interest:

Mingzhu Jin, MD: No conflicts of interest

Simon Watkins, PhD: No conflicts of interest

Yolanda Larriba, PhD: No Conflicts of Interest

Callen Wallace, PhD: No Conflicts of Interest

Claudette St. Croix, PhD: No Conflicts of Interest

Xiuxia Zhou, PhD: No Conflicts of Interest

Jinming Zhao, PhD: No Conflicts of Interest

Shyamal Peddada, PhD: No Conflicts of Interest

Sally E. Wenzel*, MD: No Conflicts of Interest directly related to this manuscript. Dr. Wenzel declares additional unrelated conflicts of interest related to consulting with Sanofi (dupilumab), AstraZeneca (Tezepelumab), GSK (mepolizumab), Knopp (dexpramipexole) and multicenter research grants with AstraZeneca (Tezepelumab and Benralizumab), GSK (anti-IL33), Knopp Bioscience (dexpramipexole). She has also received unrestricted research support for the Severe Asthma Research Program (unrelated to this study) from TEVA and Boehringer Ingelheim. She received institutional research support from Pieris.

Key Messages

IL-13 decreases AECs wound repair by delaying migration patterns. 15LO1 inhibition partially recovers the delayed wound repair.

Capsule summary

Using cutting-edge real-time confocal technology and advanced statistical methods, this article identified marked abnormalities in the wound repair and migratory patterns of asthmatic airway epithelial cells (AECs) under Type-2/IL-13 immune conditions.

Identification

DOI: https://doi.org/10.1016/j.jaci.2021.08.027

Copyright

© 2021 American Academy of Allergy, Asthma & Immunology

ScienceDirect

Access this article on ScienceDirect



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