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

ABSTRACT: 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-?B pathway and lymphotoxin-? receptor (LT?R) induced non-canonical NF-?B signaling. Indeed, LT?R costimulation synergistically enhanced the late RelA/NF-?B response to TLR4 prolonging NF-?B target gene-expressions. Concomitant LT?R 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-?B activity in a positive feedback loop. Finally, Nfkb2 connected lymphotoxin signal within the intestinal niche in reinforcing epithelial innate inflammatory RelA/NF-?B 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-?B system enables tissue microenvironment derived cues in calibrating physiological responses.

SUBMITTER: Banoth B 

PROVIDER: S-EPMC4432492 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Banoth Balaji B   Chatterjee Budhaditya B   Vijayaragavan Bharath B   Prasad M V R MV   Roy Payel P   Basak Soumen S  

eLife 20150423

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-  ...[more]

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