TSG6 hyaluronan matrix remodeling dampens the inflammatory response during colitis

Area of Science:

• Biochemistry
• Immunology
• Extracellular Matrix Biology

Background:

• Changes in the extracellular matrix (ECM) influence inflammatory responses and disease progression.
• Hyaluronan (HA) is modified by tumor necrosis factor stimulated gene-6 (TSG6) during inflammation, forming heavy chain (HC):HA complexes.
• Inflammatory bowel disease (IBD) involves ECM remodeling and leukocyte infiltration, with HC:HA matrix deposition preceding immune cell influx.

Purpose of the Study:

• To investigate the role and enzymatic activity of TSG6 in the inflammatory response within colitis models.
• To understand how TSG6-mediated modifications of the HA matrix impact intestinal inflammation and immune cell behavior.

Main Methods:

• Analysis of TSG6 and HA levels in inflamed tissues from IBD patients and control subjects.
• Assessment of acute colitis severity and immune responses in TSG6-deficient mice.
• Inhibition of TSG6's heavy chain (HC)-transferase activity and evaluation of its effects on HA stability and leukocyte adhesion.
• Biochemical generation of HC:HA complexes and assessment of their impact on activated monocyte inflammatory responses.

Main Results:

• IBD patient colon tissues exhibit elevated TSG6 and HC deposition, with HA levels correlating strongly with TSG6.
• TSG6-deficient mice show increased susceptibility to acute colitis, characterized by heightened pro-inflammatory cytokines/chemokines and reduced IL-10.
• Absence of TSG6 leads to disorganized HA matrix and reduced tissue HA levels.
• Inhibition of TSG6 HC-transferase activity disrupts cell surface HA and leukocyte adhesion.
• TSG6-derived HC:HA complexes attenuate the inflammatory response of activated monocytes.

Conclusions:

• TSG6 plays a crucial tissue-protective, anti-inflammatory role in the gut by generating HC:HA complexes.
• Dysregulation of TSG6 and its generated HC:HA complexes contributes to the pathology of inflammatory bowel disease (IBD).
• The enzymatic activity of TSG6 is essential for maintaining HA ECM stability during inflammation.