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The scaffold-dependent function of RIPK1 in dendritic cells promotes injury-induced colitis

Kenta Moriwaki1, Christa Park2,3, Kazuha Koyama4

  • 1Department of Biochemistry, Toho University School of Medicine, Ota-ku, Tokyo, Japan. kenta.moriwaki@med.toho-u.ac.jp.

Mucosal Immunology
|August 31, 2021
PubMed

Insights

Receptor interacting protein kinase 1 (RIPK1) acts as a scaffold protein to maintain gut immune balance. Loss of RIPK1 in dendritic cells causes colon inflammation, but dual RIPK3/FADD inactivation restores homeostasis.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Receptor interacting protein kinase 1 (RIPK1) is a crucial regulator of cell death and survival.
  • RIPK1's scaffold function is vital for inhibiting apoptosis and necroptosis, as evidenced by lethality in Ripk1 knockout mice.
  • RIPK1 deficiency in hematopoietic cells is linked to immunodeficiency and inflammatory bowel diseases.

Purpose of the Study:

  • To investigate the specific role of RIPK1 in dendritic cells (DCs) in maintaining intestinal immune homeostasis.
  • To elucidate the mechanisms by which RIPK1 regulates colonic inflammation.

Main Methods:

  • Generation of dendritic cell (DC)-specific Ripk1 knockout mice with inactive RIPK1 kinase activity.
  • Analysis of colonic inflammation, immune cell infiltration (neutrophils, Ly6C+ monocytes), and response to induced colitis.
  • Genetic manipulation involving dual inactivation of RIPK3 and FADD, and inhibition of RIPK3, MLKL, or ZBP1.

Main Results:

  • DC-specific Ripk1 deficiency led to spontaneous colonic inflammation with increased neutrophils and Ly6C+ monocytes.
  • These mice exhibited resistance to injury-induced colitis.
  • Colitis and resistance phenotypes were rescued by combined RIPK3 and FADD inactivation, but not by single pathway inhibition.

Conclusions:

  • RIPK1 plays a critical scaffold-dependent role in maintaining colonic immune homeostasis mediated by dendritic cells.
  • This study highlights a non-kinase function of RIPK1 in regulating intestinal inflammation.

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