PSORIASIS is a chronic inflammatory skin disorder marked by excessive epidermal proliferation, immune cell infiltration, and increased inflammatory cytokine production. Dendritic cells (DCs) play a pivotal role in the disease’s pathogenesis by mediating inflammatory responses and activating T cells, leading to the formation of psoriatic lesions. While the role of DCs in psoriasis is well established, the precise molecular mechanisms regulating their function remain unclear.
A key regulator of inflammation is the nuclear factor kappa B (NF-κB) transcription factor family, comprising RelA (p65), RelB, c-Rel, NF-κB1 (p50/p105), and NF-κB2 (p52/100). These proteins function as homo- or heterodimers and are normally sequestered in the cytoplasm by inhibitors until activation triggers their nuclear translocation for gene transcription. Among them, c-Rel is critical for the expression of several pro-inflammatory cytokines, including IL-23 and IL-12 in DCs. Studies have shown that c-Rel deficiency can mitigate autoimmune diseases such as rheumatoid arthritis and experimental autoimmune encephalomyelitis. Additionally, partial knockdown of c-Rel has been linked to reduced psoriasiform skin inflammation.
Toll-like receptors (TLRs), particularly TLR7, are key immune sensors implicated in psoriasis. TLR7 is predominantly found in endosomes, recognising single-stranded RNA and inducing inflammatory cytokine production upon activation. Imiquimod (IMQ), a synthetic TLR7 agonist, is widely used in research to induce psoriasiform skin inflammation in mice. Clinically, IMQ has been observed to exacerbate psoriasis, further highlighting the role of TLR7 signalling in disease pathogenesis. TLR7 activates the NF-κB pathway, yet the specific contribution of c-Rel in this process is not fully understood.
Recent findings indicate that c-Rel expression is upregulated in psoriatic skin lesions and decreases following treatment. Genetic deletion of c-Rel in a TLR7-induced mouse model of psoriasis resulted in a significant reduction of skin inflammation. Mechanistic studies revealed that c-Rel, along with p65, plays a central role in regulating TLR7-driven inflammation in DCs. In the absence of c-Rel, an inhibitory p50 homodimer replaces the usual c-Rel/p65 complex, suppressing key inflammatory cytokines such as IL-1β and IL-6. This leads to a reduced capacity of DCs to induce Th17 differentiation, a crucial factor in psoriasis development.
Given these findings, targeting c-Rel in DCs presents a promising therapeutic approach for psoriasis. Unlike p65 inhibition, which may have widespread effects due to its broad biological functions, c-Rel inhibition offers a more selective strategy with potentially fewer side effects. Future research, including studies using human DCs and patient-derived samples, is essential to validate these findings and explore the therapeutic potential of c-Rel inhibitors in psoriasis management.
Katie Wright, EMJ
Reference
Liu AR et al. NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasis. EBioMedicine. 2024;110:105452.
