📰 How do our lymphocytes slip and attack our intestinal flora?

© Soudja & Aoudi

Inflammatory bowel disease (IBD) is an important public health problem. It is urgent to tackle this scourge affecting many of our compatriots. In addition to the financial aspect, IBD generate diarrhea and cancer. The article, published in the journal Journal of Clinical Investigations, shows that SMAD4 is the molecular pivot of the prevention (Prevention is an attitude and/or the set of measures to be taken to avoid…) IBDs. In the absence of its activator, SMAD4 acts in opposition to it. Such Prometheus disobeying Zeus to help theMale (A man is an adult male individual of the species called Modern Man (Homo…)SMAD4 opposes its Activator for our welfare (Well-being or well-being is a state that affects health, pleasure, etc.). This duplicity within the lymphocytes will prevent IBD.

Chronic inflammatory diseases of theintestine (The intestine is the part of the digestive system that extends from the outlet of the stomach to…) (MICI) affect 3 million people in Europe (Europe is a land region that can be considered a…). Not only do they generate recurrent abdominal pain and diarrhea, but they are also fertile ground for the emergence of colorectal cancers. SMAD4, a molecule (A molecule is an electrically neutral chemical assembly of at least two atoms, which…) major signaling cytokine (Cytokines are soluble communication substances synthesized by cells…) TGF-β, is the cornerstone of the prevention ofinflammation (Inflammation is a stereotypical immune defense reaction of the…) intestinal. Unexpectedly, researchers have shown that a TGF-β-independent function of SMAD4 underlies this control (The word control can have several meanings. It can be used as a synonym of examination, of…) by preventing cytotoxic T cells from reacting uncontrollably against the flora (Flora is the set of plant species present in a space…) intestinal microbial. Thanks to numerous murine models, the researchers demonstrated that the deletion of this SMAD4 function independent of TGF-β affects the biology (Biology, commonly called « bio », is the science of life….) cytotoxic T lymphocytes at the molecular and functional level, with pathological consequences on intestinal homeostasis.

Althoughactor (An actor is an artist who embodies a character in a film, in a play, in…) key to the mediation (Since the rise of mediation in the 1980s, there have been several conceptions and…) effects of TGF-β, SMAD4, in the absence of TGF-b, represses its effects. Thus, the deletion of SMAD4 causes epigenetic, transcriptional and functional modifications opposite to the total deletion of TGF-β signaling thus revealing the duality functional (In mathematics, the term functional refers to certain functions….) of SMAD4. Ablation of TGF-β-independent SMAD4 function promotes dramatic and aberrant generation and accumulation of cytotoxic T cells in the intestinal epithelium. These uncontrollable cytotoxic T lymphocytes will generate a chronic inappropriate reaction against the microbial flora of the intestine leading to IBD. Interestingly, the placement of mouse (The term mouse is an ambiguous vernacular name which can designate, for French speakers, before…) under antibiotics protects them against this enable (Activation may refer to:) inappropriate cytotoxic T lymphocytes. Eliminating these cytotoxic lymphocytes or blocking theinteraction (An interaction is an exchange of information, affects or energy between two agents within…) with the intestinal epithelium greatly attenuates inflammation demonstrating the role of these lymphocytes in the pathology (Pathology, a term from ancient Greek, is literally the speech, the…).

This study highlights light (Light is the set of electromagnetic waves visible to the eye…) the functional duality of SMAD4 which, in the presence of the cytokine TGF-β, mediates the biological effects of TGF-β and, in its absence, inhibits them. This study provides a new perspective on the prevention of chronic inflammation of the intestine and gastrointestinal cancers, thus opening up therapeutic perspectives: antibiotic treatments, targeting of cytotoxic T lymphocytes, blocking the interaction of T lymphocytes with intestinal epithelium and finally differential targeting of each functional face of SMAD4.

Figure: Cytotoxic T lymphocytes (in green) accumulate and interact intimately with epithelial cells (blue) in the intestine. In red, proliferating cells are observed.
© Soudja & Igalouzene

To know more:
SMAD4 TGF-β-independent function preconditions naive CD8+ T cells to prevent severe chronic intestinal inflammation.
Igalouzene R, Hernandez-Vargas H, Benech N, Guyennon A, Bauché D, Barrachina C, Dubois E, Marie JC, Soudja SM.J Clin Invest. 2022 Apr 15;132(8):e151020. doi: 10.1172/JCI151020.

Laboratory:
Center of research (Scientific research designates in the first place all the actions undertaken with a view to…) in oncology (Oncology or carcinology or cancerology is the medical specialty…) of Lyon (CRCL) – (CNRS/Inserm/Lyon1 University) – 28 street (The street is a circulation space in the city that serves housing and places…) Laennec. 69373 Lyon Cedex 08.

Contact:
Saidi M’homa Soudja – Searcher (A researcher (fem. researcher) refers to a person whose job is to do research…) CNRS (The National Center for Scientific Research, better known by its acronym CNRS, is the largest…) – saidi.soudja at inserm.fr