Stimulus-selective crosstalk via the NF-κB signaling system reinforces innate immune response to alleviate gut infection
| Autor: | Payel Roy, Budhaditya Chatterjee, Soumen Basak, M V R Prasad, Bharath Vijayaragavan, Balaji Banoth |
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| Rok vydání: | 2015 |
| Předmět: |
Mice
0302 clinical medicine Intestinal mucosa lymphotoxin Intestinal Mucosa Biology (General) innate immunity Mice Knockout 0303 health sciences General Neuroscience Innate lymphoid cell Enterobacteriaceae Infections NF-kappa B General Medicine 3. Good health Cell biology 030220 oncology & carcinogenesis Medicine Signal transduction medicine.symptom Signal Transduction Research Article Computational and Systems Biology RelA:p52/NF-kappaB Cell type QH301-705.5 Science Immunology Inflammation Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Immune system NF-kappa B p52 Subunit Lymphotoxin beta Receptor medicine Animals mouse 030304 developmental biology Innate immune system General Immunology and Microbiology Transcription Factor RelA CCL18 positive feedback Immunity Innate Mice Inbred C57BL Gene Expression Regulation inflammation Citrobacter rodentium |
| Zdroj: | eLife, Vol 4 (2015) eLife |
| ISSN: | 2050-084X |
| Popis: | Tissue microenvironment functions as an important determinant of the inflammatory response elicited by the resident cells. Yet, the underlying molecular mechanisms remain obscure. Our systems-level analyses identified a duration code that instructs stimulus specific crosstalk between TLR4-activated canonical NF-κB pathway and lymphotoxin-β receptor (LTβR) induced non-canonical NF-κB signaling. Indeed, LTβR costimulation synergistically enhanced the late RelA/NF-κB response to TLR4 prolonging NF-κB target gene-expressions. Concomitant LTβR signal targeted TLR4-induced newly synthesized p100, encoded by Nfkb2, for processing into p52 that not only neutralized p100 mediated inhibitions, but potently generated RelA:p52/NF-κB activity in a positive feedback loop. Finally, Nfkb2 connected lymphotoxin signal within the intestinal niche in reinforcing epithelial innate inflammatory RelA/NF-κB response to Citrobacter rodentium infection, while Nfkb2−/− mice succumbed to gut infections owing to stromal defects. In sum, our results suggest that signal integration via the pleiotropic NF-κB system enables tissue microenvironment derived cues in calibrating physiological responses. DOI: http://dx.doi.org/10.7554/eLife.05648.001 eLife digest The innate immune system is the body's first line of defense against infection and disease. Innate immune cells are found in every tissue type, poised to respond immediately to damaged, stressed, or infected host cells. When innate immune cells recognize any injury or infection, one of the first things they do is trigger the inflammatory response. Fluid and other immune cells then move from the blood into the injured tissues. This movement can cause redness and swelling. But the response helps to establish a physical barrier against the spread of infection, promotes the elimination of both invading microbes and damaged host cells, and encourages the repair of the tissue. Inflammation is tightly controlled. If the response is too weak, it could leave an individual prone to serious infection. On the other hand, excessive inflammation can severely damage healthy cells and tissues. Inflammation is regulated differently in different tissue types, and the environment within the tissue itself influences the activity of local innate immune cells and the inflammatory response. However, the molecular mechanisms responsible for receiving and interpreting the signals derived from the host tissue remain unknown. Now, Banoth et al., have revealed that the integration of inflammation-provoking signals, such as injury or infection and cues from the tissue environment occurs via the so-called ‘NF-κB signaling system’. NF-κB is a protein found in almost all cell types, and when activated it is able to switch on the expression of many different genes. Banoth et al. explain that signal integration via the NF-κB system enables cues from the tissue environment to tune a cell's responses. Further experiments confirmed the importance of this signal integration by showing how a signal coming from intestinal tissue can influence the activity of innate immune cells and inflammation in the gut. These findings suggest that a breakdown in the NF-κB signaling system's ability to integrate multiple signals, including those derived from the tissue environment, may be responsible for many inflammatory disorders, and in particular those that involve the gut. Future work is now needed to explore this possibility. DOI: http://dx.doi.org/10.7554/eLife.05648.002 |
| Databáze: | OpenAIRE |
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