Chemokine CXCL12 drives pericyte accumulation and airway remodeling in allergic airway disease

Abstract

BACKGROUND: Airway remodeling is a significant contributor to impaired lung function in chronic allergic airway disease. Currently, no therapy exists that is capable of targeting these structural changes and the consequent loss of function. In the context of chronic allergic inflammation, pericytes have been shown to uncouple from the pulmonary microvasculature, migrate to areas of inflammation, and significantly contribute to airway wall remodeling and lung dysfunction. This study aimed to elucidate the mechanism by which pulmonary pericytes accumulate in the airway wall in a model of chronic allergic airway inflammation. METHODS: Mice were subjected to a protocol of chronic airway inflammation driven by the common environmental aeroallergen house dust mite. Phenotypic changes to lung pericytes were assessed by flow cytometry and immunostaining, and the functional capacity of these cells was evaluated using in vitro migration assays. The molecular mechanisms driving these processes were targeted pharmacologically in vivo and in vitro. RESULTS: Pericytes demonstrated increased CXCR4 expression in response to chronic allergic inflammation and migrated more readily to its cognate chemokine, CXCL12. This increase in migratory capacity was accompanied by pericyte accumulation in the airway wall, increased smooth muscle thickness, and symptoms of respiratory distress. Pericyte uncoupling from pulmonary vessels and subsequent migration to the airway wall were abrogated following topical treatment with the CXCL12 neutraligand LIT-927. CONCLUSION: These results provide new insight into the role of the CXCL12/CXCR4 signaling axis in promoting pulmonary pericyte accumulation and airway remodeling and validate a novel target to address tissue remodeling associated with chronic inflammation.

Publication DOI: https://doi.org/10.1186/s12931-022-02108-4
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
College of Health & Life Sciences > Aston Institute of Health & Neurodevelopment (AIHN)
Additional Information: © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Funding: This research was funded by the United Kingdom Medical Research Council (MR/K011375/1).
Uncontrolled Keywords: Airway Remodeling,Animals,Asthma,Chemokine CXCL12/metabolism,Disease Models, Animal,Hypersensitivity/metabolism,Inflammation/metabolism,Lung,Mice,Pericytes/metabolism,Respiration Disorders/metabolism
Publication ISSN: 1465-993X
Last Modified: 22 May 2024 07:21
Date Deposited: 14 Jul 2022 08:43
Full Text Link:
Related URLs: https://respira ... 931-022-02108-4 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2022-07-13
Published Online Date: 2022-07-13
Accepted Date: 2022-06-30
Submitted Date: 2022-03-19
Authors: Bignold, Rebecca (ORCID Profile 0000-0002-6172-418X)
Shammout, Bushra
Rowley, Jessica E.
Repici, Mariaelena (ORCID Profile 0000-0002-9420-528X)
Simms, John (ORCID Profile 0000-0002-4675-0902)
Johnson, Jill R. (ORCID Profile 0000-0002-5149-0084)

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