HomeENGLISH MAGAZINEClosing the road to gut inflammation and its "ILCs": let ZBTB46 lay...

Closing the road to gut inflammation and its “ILCs”: let ZBTB46 lay down the proper “fingers” onto it

IBD, which includes Crohn’s disease and ulcerative colitis, affects several million people in the United States. These chronic inflammatory disorders target the gut, can be seriously debilitating, and treatments may not work well for some patients—mainly because scientists don’t have a complete picture of what is driving these diseases and how the sophisticated immune cell networks in the gut support tissue health. Scientists know that there are related families of immune cells in the gut that can either protect from inflammation or at other times be major drivers of inflammation. Their network is more complex than orignally speculated before and new players are constantly found to have an intertwined molecular dialogue at several levels. It is an example the latest discovery from scientists at Jill Roberts Institute for Research in Inflammatory Bowel Disease, at Weill Cornell Medicine, led by professor Sonnernberg. According of what they published on the journal Nature a protein called Zbtb46, expressed by specialized immune cells, has a major role in protecting the gastrointestinal tract from excessive inflammation.

ZBTB46 is a zinc-finger family transcription factor with anti-oncogene properties, that has been deemed, up to now, to be exclusively expressed in dendritic cells within the immune system. Zbtb46 has also genetic links to pediatric IBD. Dr. Sonnenberg’s laboratory has been advancing the science of gut immunity with studies of recently identified immune cells called “innate lymphoid cells-3” or ILC3s. These lymphocytes are related to T cells and B cells, and clearly have important roles in protecting the gut and other organs from excess inflammation. However, in the context of IBD or colorectal cancer they become altered. The surprise of the reaserch is that, not only ZBTB46 is not exclusive for dendritic cells, but only a subset of ILCs do express the protein themselves. The experiments indicated that Zbtb46 expression normally increases in mouse ILC3s in response to inflammation. When the team examined ILC3s from the gut of children with IBD, they found higher Zbtb46 levels compared with ILC3s from healthy individuals. This is consistent with the idea that Zbtb46-expressing ILC3s have a similar role in humans as well.

Importantly, the expression level of ZBTB46 in ILC3s correlates with the severity of the disease in these sick children. Finally, the scientists found that Zbtb46-expressing ILC3s are also the main producers in the gut of a cytokine, IL-22, that protects against bacterial infection. Mice without the entire population of Zbtb46-expressing ILC3s are more susceptible to intestinal inflammation induced by gut infection. It is interesting to underline that ZBTB46 in the cytosol interacts with beta-arrestin, a protein that modulate several aspects of intracellular signalings. Beside as regulators of the desensitization and endocytosis of cell surface receptors, β-arrestin 1 and β-arrestin 2 also act as transducers and scaffolds in intracellular signals such as MAPK, PI3K/Akt, and Hck signaling pathways (this being spcific for lymphocytes). Over the last two decades, more and more evidence has indicated that β-arrestins are involved in autoimmune disease pathogenesis. For instance, the expression of β-arrestin is significantly increased in patients with rheumatoid arthritis and antibodies reactive to β-arrestins have been detectable in MS patients.

β-arrestin2 expression has been recently found to be significantly lower in active IBD than that in remissive IBD and normal subjects, and it had a negative correlation with thr expression oc CCR5, a chemokine receptor upregulated in IBD. Besides it has been founf that this protein exert protective role in colitis by modulating T lymphocyte reactivity. One signaling pathway beta-arrestin in involved into is downstream to GPR120 receptor, known to have omega-3 fatty acids as putative endogenous ligands. Through the internalization of the GPR120 complex, beta-arrestin2 enhances the activation of JNK protein kinase.  This, in turn, promotes cellular anti-inflammatory mechanisms by inhibiting NF-kB a pivotal transcription factor responsible for the expression of a plethora of pro-inflammatory proteins and cytokines. Since β-arrestin 2 is frequently anti-inflammatory in a variety of diseases, these data suggest that β-arrestin 2 may also play a role in ulcerative colitis development. All these informations may result helpful to find molecules, either natural or synthetic drugs, that would boost ZBTB46-dependent pathways in order to reach an anti-inflammatory status for IBD patients.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Boto P et al. Stem Cells 2021 Oct; 39(10):1322-1334.

Cai Y et al. J Immunol. 2019 Jan 15; 202(2):407-420.

Ye X et al. Scand J Gastroenterol 2017; 52(5):551-557.

Sharma D et al. Inflamm Bowel Dis. 2015; 21(12):2766.

Lee T, Lee E et al. Am J Pathol 2013; 182:1114–1123.

Fan H, Liao Y et al. Chin J Integr Med 2012; 18:514-21.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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