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.DOI: http://dx.doi.org/10.7554/eLife.05648.001

The NF-κB subunit RelB controls p100 processing by competing with the kinases NIK and IKK1 for binding to p100

“…Our work provides insights into how noncanonical signaling is transduced through balancing the amounts of distinct complexes with opposing activities. Increased or reduced processing of p100 causes cancer and defects in immunity (35)(36)(37)(38)(39). In all these cases, aberrant processing could be due to the defect in competition between RelB and the NIK:IKK1 complex for p100 binding as shown here.…”

Dynamics of P53 in response to DNA damage: Mathematical modeling and perspective

“…Further stochastic simulation of the delayed differential equations can recapitulate most experimental observations (Sun and Cui, 2014). This is reminiscent of the role of p100 in connecting canonical and non-canonical NF-kB signaling (Banoth et al, 2015). Noncanonical NF-kB pathway activation not only neutralized the inhibition of p100 but also produced RelA:p52/NF-kB activity (Banoth et al, 2015).…”

“…This is reminiscent of the role of p100 in connecting canonical and non-canonical NF-kB signaling (Banoth et al, 2015). Noncanonical NF-kB pathway activation not only neutralized the inhibition of p100 but also produced RelA:p52/NF-kB activity (Banoth et al, 2015). Chen et al, however, constructed another scenario where mono-and poly-ubiquitinated p53 were both considered .…”

Importance of the alternative NF-κB activation pathway in inflammation-associated gastrointestinal carcinogenesis

“…With the use of reciprocal bone marrow transfer experiments, Nfkb2 Ϫ/Ϫ mice given wild-type mouse bone marrow lost weight and had 100% mortality before day 10, whereas wild-type mice given either wild-type or Nfkb2 Ϫ/Ϫ bone marrow did not lose weight or show increased mortality. These findings indicate that NF-B2 expression within the nonmyeloid compartment is involved in limiting the severity of C. rodentium-associated colitis (10).…”

“…Using mouse embryonic fibroblasts, they demonstrated that LT␤R prolonged the TLR4-induced RelA response by targeting newly synthesized p100 for processing to p52, allowing formation of p65(RelA)-p52(NF-B2) dimers. This led to increased expression of proinflammatory cytokines and chemokines (10). Understanding the integration of different mechanisms of NF-B activation is a key challenge for this field.…”