La Trobe
biomedicines-09-00187-v2.pdf (5.88 MB)

Stat3 signalling via the il-6ST/GP130 cytokine receptor promotes epithelial integrity and intestinal barrier function during DSS-induced colitis

Download (5.88 MB)
journal contribution
posted on 30.03.2021, 00:55 by L Pang, J Huynh, Mariah Grace Alorro, Xia Li, Matthias Ernst, Ashwini Chand
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL- 6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated gp130ΔSTAT allele (GP130ΔSTAT/+), or by inducing short hairpin-mediated knockdown of Stat3 (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL- 6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients.

Funding

The study was supported by the following grants and fellowship schemes: National Medical Health and Research Council (NHMRC) of Australia (1062247, 1079257, 1092788) Cancer Council Victoria (1143036), Austin Medical Research Fund, and the Victorian Cancer Agency (19014). Institutional funding from the Victorian State Government Operational Infrastructure Support Scheme and ONJCRI is acknowledged. LP is supported by La Trobe University Full-Fee Research Scholarship and La Trobe University Postgraduate Research Scholarship.

History

Publication Date

01/02/2021

Journal

Biomedicines

Volume

9

Issue

2

Article Number

ARTN 187

Pagination

(p. 1-20)

Publisher

MDPI

ISSN

2227-9059

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.