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ABIN-2, of the TPL-2 Signaling Complex, Modulates Mammalian Inflammation

Louise V Webb1, Sonia Ventura1, Steven C Ley2

  • 1The Francis Crick Institute, London, UK.

Trends in Immunology
|August 12, 2019
PubMed

Insights

Mammalian TPL-2 kinase (MAP3K8) is crucial for immune responses. Map3k8-/- mice exhibit inflammation due to reduced ABIN-2 signaling, not blocked TPL-2 signaling, necessitating new models for TPL-2 inhibitor studies.

Area of Science:

  • Immunology
  • Molecular Biology
  • Signal Transduction

Background:

  • Mammalian TPL-2 kinase (MAP3K8) is a key regulator of Toll-like receptor-mediated immune responses, activating ERK1/2 and p38α MAP kinases.
  • TPL-2 also functions as an adaptor protein, stabilizing the ABIN-2 ubiquitin-binding protein, meaning Map3k8-/- mouse phenotypes can result from loss of TPL-2, ABIN-2, or both.

Purpose of the Study:

  • To address the confounding effects of ABIN-2 loss in Map3k8-/- mice when evaluating TPL-2 as an anti-inflammatory drug target.
  • To propose a refined mouse model for accurately assessing the therapeutic potential of TPL-2 inhibitors in inflammatory diseases.

Main Methods:

  • Utilizing Map3k8D270A/D270A mice, which express a catalytically inactive form of TPL-2 while maintaining physiological levels of ABIN-2.
  • Comparing inflammatory phenotypes in Map3k8D270A/D270A mice with those in Map3k8-/- mice.

Main Results:

  • Recent studies indicate that inflammation in Map3k8-/- mice, observed in allergic airway inflammation and colitis models, is primarily due to diminished ABIN-2 signaling rather than impaired TPL-2 kinase activity.
  • This suggests that Map3k8-/- mice are not ideal for studying the specific effects of TPL-2 inhibition.

Conclusions:

  • The use of Map3k8-/- mice to investigate TPL-2's role in inflammation and as a drug target is potentially misleading due to the concurrent loss of ABIN-2.
  • Map3k8D270A/D270A mice represent a more appropriate model for evaluating the efficacy and safety of TPL-2 inhibitors, as they isolate the kinase's activity from ABIN-2's function.

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