MTDH Promotes Intestinal Inflammation by Positively Regulating TLR Signalling

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Toll-like receptor (TLR)-mediated inflammation in intestinal macrophages is crucial for pathogen defense but can cause colitis.
• Metadherin (MTDH) is known for its role in cancer progression, but its function in intestinal inflammation is unclear.

Purpose of the Study:

• To investigate the role of MTDH in the development of inflammatory colitis.
• To elucidate the molecular mechanisms by which MTDH influences TLR-induced inflammatory responses in macrophages.

Main Methods:

• Assessed MTDH expression in colonic lamina propria (CLP) macrophages from colitis patients.
• Utilized MTDH knockout (MTDH-/-) mice and wild-type (WT) mice in dextran sodium sulfate (DSS)-induced colitis models.
• Performed adoptive transfer experiments with MTDH WT monocytes into MTDH-/- mice.
• Investigated the effect of TLR stimulation on MTDH expression and cytokine production in macrophages.
• Examined the molecular interaction of MTDH with TRAF6 and TAK1, and its effect on NF-κB and MAPK signaling pathways.

Main Results:

• MTDH expression in CLP macrophages correlated positively with colitis severity.
• MTDH-/- mice showed protection against DSS-induced colitis.
• Adoptive transfer of MTDH WT monocytes partially restored colitis susceptibility in MTDH-/- mice.
• TLR stimulation induced MTDH expression, while MTDH absence suppressed TLR-induced inflammatory cytokine production.
• MTDH was found to recruit TRAF6 to TAK1, promoting TAK1 ubiquitination and phosphorylation, thereby enhancing TLR-induced NF-κB and MAPK signaling.

Conclusions:

• MTDH plays a significant role in promoting colitis development by enhancing TLR-induced pro-inflammatory cytokine production in CLP macrophages.
• MTDH represents a potential therapeutic target for intervening in intestinal inflammation.