Cutting Edge: NF-kB p65 and c-Rel Control Epidermal Development and Immune Homeostasis in the Skin

Psoriasis is an inflammatory skin disease in which activated immune cells and the proinflammatory cytokine TNF are well-known mediators of pathogenesis. The transcription factor NF-kB is a key regulator of TNF production and TNF-induced proinflammatory gene expression, and both the psoriatic transcriptome and genetic susceptibility further implicate NF-kB in pso-riasis etiopathology. However, the role of NF-kB in psoriasis remains controversial. We analyzed the function of canonical NF-kB in the epidermis using CRE-mediated deletion of p65 and c-Rel in keratinocytes. In contrast to animals lacking p65 or c-Rel alone, mice lacking both subunits developed severe dermatitis after birth. Consistent with its partial histological similarity to human psoriasis, this condition could be prevented by anti-TNF treatment. Moreover, regulatory T cells in lesional skin played an important role in disease remission. Our results demonstrate that canonical NF-kB in keratinocytes is essential for the maintenance of skin immune homeostasis and is protective against spontaneous dermatitis. P soriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia, altered keratinocyte differentiation, and inflammatory infiltrates (1). It remains unclear whether the primary defect fomenting pso-riasis lesion development affects keratinocytes or immune cell function. In murine models, forced expression of inflamma-tory cytokines in keratinocytes produces lesions with characteristics of human psoriasis (2–4). Constitutive activation of several transcription factors that regulate the expression of inflammatory cytokines, such as STAT-3 or NF-kB in kera-tinocytes or immune cells, also can drive cutaneous inflammation (5, 6). The transcription factor NF-kB is a complex formed by dimerization of its subunits: p65 (RelA), RelB, c-Rel, p50, and p52 (7). The canonical NF-kB pathway culminates in activation of dimers of p65, c-Rel, and p50 subunits. Genome-wide association studies suggest a link between psoriasis and the NF-kB pathway (8) that is supported by mouse models. Ablation of the NF-kB inhibitor IkBa produces cutaneous inflammation and keratinocyte proliferation (6, 9). However, deletion of IKKb, which mediates canonical NF-kB activation, produces a fulminant psoriasis-like disease in mice (10). Expression of an IkBa superrepressor in kera-tinocytes also results in a similar, although less severe, phenotype (11). These phenotypes are driven by TNF, because IKKb-deficient mice lacking TNFR1 or treated with anti-TNF Abs do not develop the disease (10, 12, 13). Given that IkBa has NF-kB–independent functions in keratinocyte development (14), and IKKb has direct effects on ERK and STAT1 activation (15–17), it is unclear whether the cutane-ous inflammation in these mice is fully attributable to defective NF-kB activation. …