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

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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.

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Balaji Banoth

Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India

Competing interests
The authors declare that no competing interests exist.
Budhaditya Chatterjee

Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India

Competing interests
The authors declare that no competing interests exist.
Bharath Vijayaragavan

Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India

Competing interests
The authors declare that no competing interests exist.
M V R Prasad

Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India

Competing interests
The authors declare that no competing interests exist.
Payel Roy

Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India

Competing interests
The authors declare that no competing interests exist.
Soumen Basak

Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India

For correspondence
sobasak@nii.ac.in

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: Wild-type or gene-deficient C57BL/6 mice were housed at NII small animal facility and used strictly in accordance with the Institutional Animal Ethics Committee guidelines of the institute. The protocol was approved by the committee with the approved protocol no: IAEC#258/11 (for embryonic fibroblast cell collection) and IAEC#313/13 (for infection related studies).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.