MTDH Promotes Intestinal Inflammation by Positively Regulating TLR Signalling.

Abstract

Macrophages in the intestinal mucosa can rapidly engage Toll-like receptor [TLR]-mediated inflammatory responses to protect against pathogen invasion, but these same innate immune responses can also drive the induction of colitis. Our previous research revealed that metadherin [MTDH] is overexpressed in multiple cancers and plays vital roles in tumour progression. However, the role of MTDH in intestinal inflammation is largely unknown. In this study, we found the MTDH expression in colonic lamina propria [CLP] macrophages was positively correlated with inflammatory colitis severity. MTDH-/- mice were protected against the symptoms of dextran sodium sulphate [DSS]-induced colitis; however, adoptive transfer of MTDH wild-type [WT] monocytes partially restored the susceptibility of MTDH-/- mice to DSS-induced colitis. TLR stimulation was sufficient to induce the expression of MTDH, whereas the absence of MTDH was sufficient to suppress TLR-induced production of inflammatory cytokines by macrophages. From a mechanistic perspective, MTDH recruited TRAF6 to TAK1, leading to TRAF6-mediated TAK1 K63 ubiquitination and phosphorylation, ultimately facilitating TLR-induced NF-κB and MAPK signalling. Taken together, our results indicate that MTDH contributes to colitis development by promoting TLR-induced pro-inflammatory cytokine production in CLP macrophages and might represent a potential therapeutic approach for intestine inflammation intervention.

• Authors: Lijuan Wang, Ning Zhang, Dianwen Han, Peng Su, Bing Chen, Wenjing Zhao, Ying Liu, Hanwen Zhang, Guohong Hu, Qifeng Yang
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 15 Issue 12 Pg. 2103-2117 (Dec 18 2021) ISSN: 1876-4479 [Electronic] England
• PMID: 33987665 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Membrane Proteins
• Mtdh protein, mouse
• RNA-Binding Proteins
• Toll-Like Receptors

Topics

• Animals
• Colitis, Ulcerative (metabolism, pathology)
• Disease Models, Animal
• Female
• Inflammation
• Macrophages
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• RNA-Binding Proteins (metabolism)
• Severity of Illness Index
• Toll-Like Receptors (metabolism)