title: 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.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Balaji
authors.initials: B
authors.lastname: Banoth
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Budhaditya
authors.initials: B
authors.lastname: Chatterjee
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Bharath
authors.initials: B
authors.lastname: Vijayaragavan
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: M V R
authors.initials: MV
authors.lastname: Prasad
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Payel
authors.initials: P
authors.lastname: Roy
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Soumen
authors.initials: S
authors.lastname: Basak
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium / Q000276:immunology* / Q000472:pathogenicity; D004756:Enterobacteriaceae Infections / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics*; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology; D052003:NF-kappa B p52 Subunit / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology
chemical_list: D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; C498207:Nfkb2 protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA
keywords: Citrobacter rodentium; RelA:p52/NF-kappaB; computational biology; immunology; inflammation; innate immunity; lymphotoxin; mouse; positive feedback; systems biology