A TNF‐p100 pathway subverts noncanonical NF‐κB signaling in inflamed secondary lymphoid organs. (23rd October 2017)

• Record Type: Journal Article
• Authors: Mukherjee, Tapas; Chatterjee, Budhaditya; Dhar, Atika; Bais, Sachendra S; Chawla, Meenakshi; Roy, Payel; George, Anna; Bal, Vineeta; Rath, Satyajit; Basak, Soumen
• Is Part Of: EMBO journal. Volume 36:Number 23(2017)
• Page Start: 3501
• Page End: 3516
• Publication Date: 2017-10-23
• Subjects: homeostatic chemokine -- inhibition -- lymphocyte trafficking -- noncanonical NF‐kappaB -- TNF; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201796919
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Lymphotoxin‐beta receptor (LTβR) present on stromal cells engages the noncanonical NF‐κB 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‐κB 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 IκBδ. 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. Synopsis: Noncanonical NF‐κB signaling produces homeostatic chemokines, which direct naïve lymphocytes into secondary lymphoid organs (SLOs). TNF accumulation in inflamed SLOs alters this homeostasis by subverting noncanonical signaling. LTβR‐stimulated noncanonical RelB NF‐κB signaling produces homeostatic chemokines in SLOs. TNF abrogates LTβR‐stimulated noncanonical RelB activity. TNF inhibits NIK and induces the production inhibitory p100‐IκBδ. A TNF‐p100 pathway downregulates homeostatic chemokines in inflamed SLOs. Abstract : Depletion of homeostatic chemokines associated with microbial infection is also observed during non‐infectious and chronic inflammation, resulting in diminished lymphocyte trafficking.