Stimulus-selective crosstalk via the NF-κB 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-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.

• Authors: Balaji Banoth, Budhaditya Chatterjee, Bharath Vijayaragavan, M V R Prasad, Payel Roy, Soumen Basak
• Journal: eLife (Elife) Vol. 4 (Apr 23 2015) ISSN: 2050-084X [Electronic] England
• PMID: 25905673 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lymphotoxin beta Receptor
• NF-kappa B
• NF-kappa B p52 Subunit
• Nfkb2 protein, mouse
• Rela protein, mouse
• Transcription Factor RelA

Topics

• Animals
• Citrobacter rodentium (immunology, pathogenicity)
• Enterobacteriaceae Infections (immunology)
• Gene Expression Regulation (immunology)
• Immunity, Innate (genetics)
• Inflammation (genetics)
• Intestinal Mucosa (immunology, microbiology)
• Lymphotoxin beta Receptor (genetics, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (genetics, immunology)
• NF-kappa B p52 Subunit (deficiency, genetics)
• Signal Transduction (genetics)
• Transcription Factor RelA (genetics, immunology)