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

eLife

Budhaditya Chatterjee¹  Bharath Vijayaragavan¹  Balaji Banoth¹  MVR Prasad¹  Payel Roy¹  Soumen Basak¹ 

[1] Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India;

关键词: inflammation;    innate immunity;    lymphotoxin;    Citrobacter rodentium;    positive feedback;    RelA:p52/NF-kappaB;   

DOI  :  10.7554/eLife.05648

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown