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

Graphical AbstractHighlights d Increased expression of Cadm4 in oligodendrocytes inhibits myelination d Axoglial interaction mediated by Cadm proteins regulate myelin targeting d Myelination requires tightly regulated axoglial adhesion SUMMARYThe initiation of axoglial contact is considered a prerequisite for myelination, yet the role cell adhesion molecules (CAMs) play in mediating such interactions remains unclear. To examine the function of axoglial CAMs, we tested whether enhanced CAMmediated adhesion between OLs and neurons could affect myelination. Here we show that increased expression of a membrane-bound extracellular domain of Cadm4 (Cadm4dCT) in cultured oligodendrocytes results in the production of numerous axoglial contact sites that fail to elongate and generate mature myelin. Transgenic mice expressing Cadm4dCT were hypomyelinated and exhibit multiple myelin abnormalities, including myelination of neuronal somata. These abnormalities depend on specific neuron-glial interaction as they were not observed when these OLs were cultured alone, on nanofibers, or on neurons isolated from mice lacking the axonal receptors of Cadm4. Our results demonstrate that tightly regulated axon-glia adhesion is essential for proper myelin targeting and subsequent membrane wrapping and lateral extension.

Environmental drug resistance constitutes a serious impediment for therapeutic intervention in multiple myeloma. Tumor promoting cytokines, such as TNF, induce NFκB driven expression of pro-survival factors, which confer resistance in myeloma cells to apoptotic insults from TRAIL and other chemotherapeutic drugs. It is thought that RelA:p50 dimer, activated from IκBα-inhibited complex in response to TNF-induced canonical NFκB signal, mediates the pro-survival NFκB function in cancerous cells. Myeloma cells additionally acquire gain-of-function mutations in the non-canonical NFκB module, which induces partial proteolysis of p100 into p52 to promote RelB:p52/NFκB activation from p100-inhibited complex during immune cell-differentiation. However, role of non-canonical NFκB signaling in the drug resistance in multiple myeloma remains unclear. Here we report that myeloma-associated non-canonical aberrations reinforce pro-survival TNF signaling in producing a protracted TRAIL-refractory state. These mutations did not act through typical p52 NFκB complex, but completely degraded p100 to reposition RelB under IκBα control, whose degradation during TNF signaling induced an early RelB:p50 containing NFκB activity. More so, autoregulatory RelB synthesis prolonged this TNF-induced RelB:p50 activity in myeloma cells harboring non-canonical mutations. Intriguingly, TNF-activated RelB:p50 dimer was both necessary and sufficient, and RelA was not required, for NFκB dependent pro-survival gene-expressions and suppression of apoptosis. Indeed, high RelB mRNA expressions in myeloma patients correlated with the augmented level of pro-survival factors and resistance to therapeutic intervention. In sum, we provide evidence that cancer-associated mutations perpetuate TNF-induced pro-survival NFκB activity through autoregulatory RelB control and thereby exacerbate environmental drug-resistance in multiple myeloma.

WOREE syndrome caused by human germline biallelic mutations in WWOX is a neurodevelopmental disorder characterized by intractable epilepsy, severe developmental delay, ataxia and premature death at the age of 2–4 years. The underlying mechanisms of WWOX actions are poorly understood. In the current study, we show that specific neuronal deletion of murine Wwox produces phenotypes typical of the Wwox-null mutation leading to brain hyperexcitability, intractable epilepsy, ataxia and postnatal lethality. A significant decrease in transcript levels of genes involved in myelination was observed in mouse cortex and hippocampus. Wwox-mutant mice exhibited reduced maturation of oligodendrocytes, reduced myelinated axons and impaired axonal conductivity. Brain hyperexcitability and hypomyelination were also revealed in human brain organoids with a WWOX deletion. These findings provide cellular and molecular evidence for myelination defects and hyperexcitability in the WOREE syndrome linked to neuronal function of WWOX.