A TNF-p100 pathway subverts noncanonical NF-{kappa}B signaling in inflamed secondary lymphoid organs

Lymphotoxin-beta receptor (LTβR) present on stromal cells engages the noncanonical NF-B pathway to mediate RelB-dependent expressions of homeostatic chemokines, which direct steady-state ingress of naïve lymphocytes to secondary lymphoid organs (SLOs). In this pathway, NIK promotes partial proteolysis of p100 into p52 that induces nuclear translocation of the RelB NF-B heterodimers. Microbial infections often deplete homeostatic chemokines; it is thought that infection-inflicted destruction of stromal cells results in the downregulation of these chemokines. Whether inflammation per se also regulates these processes remains unclear. We show that TNF accumulated upon non-infectious immunization of mice similarly downregulates the expressions of these chemokines and consequently diminishes the ingress of naïve lymphocytes in inflamed SLOs. Mechanistically, TNF inactivated NIK in LTβR-stimulated cells and induced the synthesis of Nfkb2 mRNA encoding p100; these together potently accumulated unprocessed p100, which attenuated the RelB activity as inhibitory IB. Finally, a lack of p100 alleviated these TNF-mediated inhibitions in inflamed SLOs of immunized Nfkb2–/– mice. In sum, we reveal that an inhibitory TNF-p100 pathway modulates the adaptive compartment during immune responses.

Source: EMBO Journal - December 1, 2017 Category: Molecular Biology Authors: Mukherjee, T., Chatterjee, B., Dhar, A., Bais, S. S., Chawla, M., Roy, P., George, A., Bal, V., Rath, S., Basak, S. Tags: Immunology, Signal Transduction Articles Source Type: research