Stimulus-selective crosstalk via the NF-κB signaling system reinforces innate immune response to alleviate gut infection

• Main Authors: Balaji Banoth, Budhaditya Chatterjee, Bharath Vijayaragavan, MVR Prasad, Payel Roy, Soumen Basak
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2015-04-01
• Series: eLife
• Subjects: inflammation; innate immunity; lymphotoxin; Citrobacter rodentium; positive feedback; RelA:p52/NF-kappaB
• Online Access: https://elifesciences.org/articles/05648

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.