Nuclear factor kappa B (NF-κB) c-Rel is a psoriasis susceptibility locus, however mechanisms underlying c-Rel transactivation during disease are poorly understood. Inflammation in psoriasis can be triggered following Toll-like Receptor 7 (TLR7) signalling in dendritic cells (DCs), and c-Rel is a critical regulator of DC function. Here, we studied the mechanism of TLR7-induced c-Rel-mediated inflammation in DCs.
The overall expression of c-Rel was analysed in skin sections from patients with psoriasis in human transcriptomics datasets as well as the imiquimod-induced psoriasis mouse model. The function of c-Rel in DCs following TLR7 stimulation was determined by c-Rel CRISPR/Cas9 knockout DC2.4 immortalised cells and primary bone marrow derived dendritic cells from c-Rel knockout C57BL6/J mice.
c-Rel is highly expressed in lesional skin of patients with psoriasis and TLR7-induced psoriatic lesions in mice. c-Rel deficiency protected mice from the disease, and specifically compromised TLR7-induced, and not TLR9- or TLR3-induced, inflammation in dendritic cells. Mechanistically, c-Rel deficiency disrupted activating NF-κB dimers and allowed binding of inhibitory NF-κB homodimers to the IL-1β and IL-6 promoters thus inhibiting their expression. This functionally compromises the ability of c-Rel deficient DCs to induce Th17 polarisation, which is critical in psoriasis pathogenesis.
Our findings reveal that c-Rel is a key regulator of TLR7-mediated dendritic cell-dependent inflammation, and that targeting c-Rel-dependent signalling could prove an effective strategy to dampen excessive inflammation in TLR7-related skin inflammation.
A complete list of funding sources that contributed to this study can be found in the Acknowledgements section.
Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.

We hypothesize that innate immune signals from infectious organisms and/or injured tissues may activate peripheral neuronal pain signals. In this study, we demonstrated that TLRs 3, 7, and 9 are expressed by human dorsal root ganglion neurons (DRGNs) and in cultures of primary mouse DRGNs. Stimulation of murine DRGNs with TLR ligands induced expression and production of proinflammatory chemokines and cytokines CCL5 (RANTES), CXCL10 (IP-10), IL-1α, IL-1β, and PGE(2), which have previously been shown to augment pain. Further, TLR ligands upregulated the expression of a nociceptive receptor, transient receptor potential vanilloid type 1 (TRPV1), and enhanced calcium flux by TRPV1-expressing DRGNs. Using a tumor-induced temperature sensitivity model, we showed that in vivo administration of a TLR9 antagonist, known as a suppressive oligodeoxynucleotide, blocked tumor-induced temperature sensitivity. Taken together, these data indicate that stimulation of peripheral neurons by TLR ligands can induce nerve pain.