UMMS Affiliation

Department of Pathology; Graduate School of Biomedical Sciences, Immunology and Microbiology Program

Publication Date

2022-01-15

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cell Biology | Cellular and Molecular Physiology | Digestive System Diseases | Enzymes and Coenzymes | Immunopathology

Abstract

Receptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death. While RIPK1 promotes cell death through its kinase activity, it also functions as a scaffold protein to promote cell survival by inhibiting FADD-caspase 8-dependent apoptosis and RIPK3-MLKL-dependent necroptosis. This pro-survival function is highlighted by excess cell death and perinatal lethality in Ripk1(-/-) mice. Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. Hematopoietic stem cell transplantation restored not only immunodeficiency but also intestinal inflammatory pathology, indicating that RIPK1 in hematopoietic cells is critical to maintain intestinal immune homeostasis. Here, we generated dendritic cell (DC)-specific Ripk1(-/-) mice in a genetic background with loss of RIPK1 kinase activity and found that the mice developed spontaneous colonic inflammation characterized by increased neutrophil and Ly6C(+) monocytes. In addition, these mice were highly resistant to injury-induced colitis. The increased colonic inflammation and the resistance to colitis were restored by dual inactivation of RIPK3 and FADD, but not by inhibition of RIPK3, MLKL, or ZBP1 alone. Altogether, these results reveal a scaffold activity-dependent role of RIPK1 in DC-mediated maintenance of colonic immune homeostasis.

Keywords

RIPK1, colitis

Rights and Permissions

Copyright © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

DOI of Published Version

10.1038/s41385-021-00446-y

Source

Moriwaki K, Park C, Koyama K, Balaji S, Kita K, Yagi R, Komazawa-Sakon S, Semba M, Asuka T, Nakano H, Kamada Y, Miyoshi E, Chan FKM. The scaffold-dependent function of RIPK1 in dendritic cells promotes injury-induced colitis. Mucosal Immunol. 2022 Jan;15(1):84-95. doi: 10.1038/s41385-021-00446-y. Epub 2021 Aug 30. PMID: 34462571; PMCID: PMC8732271. Link to article on publisher's site

Journal/Book/Conference Title

Mucosal immunology

Related Resources

Link to Article in PubMed

PubMed ID

34462571

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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