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Murine Colitis Modeling using Dextran Sulfate Sodium DSS
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ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism

Sambit K Nanda1, Tsunehisa Nagamori1, Mark Windheim1

  • 1Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom.

Journal of Immunology (Baltimore, Md. : 1950)
|October 26, 2018
PubMed

Insights

The A20-binding inhibitor of NF-κB 2 (ABIN2) mutant mice show intestinal inflammation, suggesting ABIN2

Area of Science:

  • Immunology
  • Molecular Biology
  • Inflammation Research

Background:

  • A20-binding inhibitor of NF-κB 2 (ABIN2) interacts with Met1-linked ubiquitin chains and is part of the tumor progression locus 2 (Tpl2) kinase complex.
  • The role of ABIN2's ubiquitin-binding function in Tpl2 complex stability and activation is not fully understood.
  • ABIN2's contribution to inflammatory responses, particularly in the context of colitis, requires further investigation.

Purpose of the Study:

  • To investigate the role of ABIN2's ubiquitin-binding activity in Tpl2 kinase complex function.
  • To determine the in vivo function of ABIN2 in intestinal inflammation and dextran sodium sulfate (DSS)-induced colitis.
  • To elucidate the mechanism by which ABIN2 influences inflammatory mediator production in intestinal myofibroblasts (IMFs).

Main Methods:

  • Generation of a knock-in mouse model expressing a ubiquitin-binding-defective ABIN2 mutant (ABIN2[D310N]).
  • Assessment of Tpl2 expression and activation in macrophages and fibroblasts from ABIN2[D310N] mice.
  • Induction of colitis using dextran sodium sulfate (DSS) in ABIN2[D310N] mice and analysis of inflammatory cell populations.
  • Measurement of cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) production in response to IL-1β stimulation in mouse embryonic fibroblasts and IMFs.

Main Results:

  • ABIN2[D310N] mutation did not affect Tpl2 expression or activation, indicating ubiquitin binding is dispensable for Tpl2 stability and function.
  • ABIN2[D310N] mice exhibited spontaneous intestinal inflammation and heightened sensitivity to DSS-induced colitis, mediated by radiation-resistant cells.
  • IL-1β-induced COX2 expression and PGE2 secretion were significantly reduced in fibroblasts and IMFs from ABIN2[D310N] mice.
  • The observed reduction in COX2 and PGE2 production in ABIN2[D310N] mice mimics Tpl2 knockout phenotypes but occurs independently of Tpl2 kinase activity.

Conclusions:

  • ABIN2's interaction with ubiquitin chains is not essential for Tpl2 kinase complex stability or activation.
  • ABIN2 plays a critical role in regulating intestinal inflammation and colitis susceptibility, independent of Tpl2 kinase activity.
  • The loss of ABIN2 impairs COX2 and PGE2 production in IMFs via a Tpl2-independent pathway, contributing to colitis severity.

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