A TNF-p100 pathway subverts noncanonical NF-κB signaling in inflamed secondary lymphoid organs.

Autor: Mukherjee T; Systems Immunology Laboratory National Institute of Immunology, New Delhi, India.; National Institute of Immunology, New Delhi, India., Chatterjee B; Systems Immunology Laboratory National Institute of Immunology, New Delhi, India.; Kusuma School of Biological Sciences, IIT-Delhi, New Delhi, India., Dhar A; National Institute of Immunology, New Delhi, India., Bais SS; Systems Immunology Laboratory National Institute of Immunology, New Delhi, India.; National Institute of Immunology, New Delhi, India., Chawla M; Systems Immunology Laboratory National Institute of Immunology, New Delhi, India.; National Institute of Immunology, New Delhi, India., Roy P; Systems Immunology Laboratory National Institute of Immunology, New Delhi, India.; National Institute of Immunology, New Delhi, India., George A; National Institute of Immunology, New Delhi, India., Bal V; National Institute of Immunology, New Delhi, India., Rath S; National Institute of Immunology, New Delhi, India., Basak S; Systems Immunology Laboratory National Institute of Immunology, New Delhi, India sobasak@nii.ac.in.; National Institute of Immunology, New Delhi, India.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2017 Dec 01; Vol. 36 (23), pp. 3501-3516. Date of Electronic Publication: 2017 Oct 23.
DOI: 10.15252/embj.201796919
Abstrakt: 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.
(© 2017 The Authors.)
Databáze: MEDLINE
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