NF-κB Inducing Kinase Regulates Intestinal Immunity and Homeostasis

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Jul 14

PMID 35833111

Authors

Bingran Wang

Jun Shen

Affiliations

Soon will be listed here.

Abstract

Intestinal immunity and homeostasis are maintained through the regulation of cytokine trafficking, microbiota, necrosis and apoptosis. Intestinal immunity and homeostasis participate in host defenses and inflammatory responses locally or systemically through the gut-organ axis. NF-κB functions as a crucial transcription factor mediating the expression of proteins related to the immune responses. The activation of NF-κB involves two major pathways: canonical and non-canonical. The canonical pathway has been extensively studied and reviewed. Here, we present the current knowledge of NIK, a pivotal mediator of the non-canonical NF-κB pathway and its role in intestinal immunity and homeostasis. This review also discusses the novel role of NIK signaling in the pathogenesis and treatment of inflammatory bowel disease.

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References

Al-Sadi R, Guo S, Ye D, Rawat M, Ma T . TNF-α Modulation of Intestinal Tight Junction Permeability Is Mediated by NIK/IKK-α Axis Activation of the Canonical NF-κB Pathway. Am J Pathol. 2016; 186(5):1151-65. PMC: 4861759. DOI: 10.1016/j.ajpath.2015.12.016. View

Chen X, Willette-Brown J, Wu X, Hu Y, Howard O, Hu Y . IKKα is required for the homeostasis of regulatory T cells and for the expansion of both regulatory and effector CD4 T cells. FASEB J. 2014; 29(2):443-54. PMC: 4314223. DOI: 10.1096/fj.14-259564. View

Ramakrishnan S, Zhang H, Ma X, Jung I, Schwartz A, Triner D . Intestinal non-canonical NFκB signaling shapes the local and systemic immune response. Nat Commun. 2019; 10(1):660. PMC: 6368617. DOI: 10.1038/s41467-019-08581-8. View

Zhang S, Breidenbach J, Russell B, George J, Haller S . CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease. J Clin Med. 2020; 9(11). PMC: 7697100. DOI: 10.3390/jcm9113653. View

Bartuzi P, Hofker M, van de Sluis B . Tuning NF-κB activity: a touch of COMMD proteins. Biochim Biophys Acta. 2013; 1832(12):2315-21. DOI: 10.1016/j.bbadis.2013.09.014. View

Egawa T, Kawabata K, Kawamoto H, Amada K, Okamoto R, Fujii N . The earliest stages of B cell development require a chemokine stromal cell-derived factor/pre-B cell growth-stimulating factor. Immunity. 2001; 15(2):323-34. DOI: 10.1016/s1074-7613(01)00185-6. View

Gray C, McCorkell K, Chunduru S, McKinlay M, May M . Negative feedback regulation of NF-κB-inducing kinase is proteasome-dependent but does not require cellular inhibitors of apoptosis. Biochem Biophys Res Commun. 2014; 450(1):341-6. PMC: 4107106. DOI: 10.1016/j.bbrc.2014.05.122. View

Gantke T, Sriskantharajah S, Sadowski M, Ley S . IκB kinase regulation of the TPL-2/ERK MAPK pathway. Immunol Rev. 2012; 246(1):168-82. DOI: 10.1111/j.1600-065X.2012.01104.x. View

Zarnegar B, Wang Y, Mahoney D, Dempsey P, Cheung H, He J . Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008; 9(12):1371-8. PMC: 2676931. DOI: 10.1038/ni.1676. View

10.

Hofer S, Rescigno M, Granucci F, Citterio S, Francolini M, Ricciardi-Castagnoli P . Differential activation of NF-kappa B subunits in dendritic cells in response to Gram-negative bacteria and to lipopolysaccharide. Microbes Infect. 2001; 3(4):259-65. DOI: 10.1016/s1286-4579(01)01378-8. View

11.

Han D, Walsh M, Cejas P, Dang N, Kim Y, Kim J . Dendritic cell expression of the signaling molecule TRAF6 is critical for gut microbiota-dependent immune tolerance. Immunity. 2013; 38(6):1211-22. PMC: 3715143. DOI: 10.1016/j.immuni.2013.05.012. View

12.

Morrison M, Reiley W, Zhang M, Sun S . An atypical tumor necrosis factor (TNF) receptor-associated factor-binding motif of B cell-activating factor belonging to the TNF family (BAFF) receptor mediates induction of the noncanonical NF-kappaB signaling pathway. J Biol Chem. 2005; 280(11):10018-24. DOI: 10.1074/jbc.M413634200. View

13.

Sethi G, Sung B, Aggarwal B . Nuclear factor-kappaB activation: from bench to bedside. Exp Biol Med (Maywood). 2007; 233(1):21-31. DOI: 10.3181/0707-MR-196. View

14.

Dejardin E, Droin N, Delhase M, Haas E, Cao Y, Makris C . The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity. 2002; 17(4):525-35. DOI: 10.1016/s1074-7613(02)00423-5. View

15.

Yousefi B, Eslami M, Ghasemian A, Kokhaei P, Salek Farrokhi A, Darabi N . Probiotics importance and their immunomodulatory properties. J Cell Physiol. 2018; 234(6):8008-8018. DOI: 10.1002/jcp.27559. View

16.

Schutyser E, Struyf S, Van Damme J . The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev. 2003; 14(5):409-26. DOI: 10.1016/s1359-6101(03)00049-2. View

17.

Bruewer M, Utech M, Ivanov A, Hopkins A, Parkos C, Nusrat A . Interferon-gamma induces internalization of epithelial tight junction proteins via a macropinocytosis-like process. FASEB J. 2005; 19(8):923-33. DOI: 10.1096/fj.04-3260com. View

18.

Jung J, Ravi S, Lee D, McFadden K, Kamradt M, Toussaint L . NIK/MAP3K14 Regulates Mitochondrial Dynamics and Trafficking to Promote Cell Invasion. Curr Biol. 2016; 26(24):3288-3302. PMC: 5702063. DOI: 10.1016/j.cub.2016.10.009. View

19.

Suzuki T . Regulation of the intestinal barrier by nutrients: The role of tight junctions. Anim Sci J. 2020; 91(1):e13357. PMC: 7187240. DOI: 10.1111/asj.13357. View

20.

Rey J, Garin N, Spertini F, Corthesy B . Targeting of secretory IgA to Peyer's patch dendritic and T cells after transport by intestinal M cells. J Immunol. 2004; 172(5):3026-33. DOI: 10.4049/jimmunol.172.5.3026. View