IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes

Abstract

SignificancePsoriasis is an autoinflammatory disease characterized by cytokine-driven keratinocyte proliferation and infiltration of immune cells. While IL-17A and TNFα are established targets in psoriasis therapy, IL-36 is emerging as an important cytokine in this disease. The mechanisms of IL-36–driven proinflammatory responses are largely unknown. Here we identified IκBζ, a transcriptional regulator of selective NF-κB target genes, as a crucial mediator of IL-36 action. In keratinocytes, IκBζ was required for the expression of several psoriasis-related cytokines and chemokines. Moreover, genetic deletion of IκBζ prevented IL-36–mediated dermatitis induction in mice. Since IκBζ is essential not only for IL-36 but also for IL-17 signaling, our results suggest that inhibition of IκBζ function could be a future strategy in psoriasis therapy.

Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation

“…For this reason, we investigated IL-36-mediated psoriasis in mice lacking IκBζ in keratinocytes because IL-36 is believed to trigger psoriasis through chronic activation of keratinocytes. As shown before (8), intradermal injections of biologically active IL-36α for 5 consecutive days induced psoriasis-like dermatitis in control mice, including keratinocyte hyperproliferation as well as massive infiltration of neutrophils, macrophages, and T cells ( Figure 4, A-C). In line with the IMQ model, keratinocyte-specific Nfkbiz-KO mice were completely protected against IL-36-induced ear swelling, hyperkeratosis ( Figure 4, A and B), as well as infiltration of neutrophils and macrophages ( Figure 4C).…”

“…Although IκBζ constitutes a key transcriptional regulator driving the onset of psoriasis, the cell type(s) in which IκBζ is induced to exert its psoriasis-promoting function remains unclear. Because of its function in mediating IL-17A expression in T H 17 cells as well as its role as a downstream mediator of IL-17A and IL-36 signaling in keratinocytes (7,8,16,19), it is speculated that induction of IκBζ in one of these cell types is responsible for the development of psoriasis. To answer this question, we generated keratinocyte-specific Nfkbiz-deficient mice and analyzed IMQ-induced psoriasis.…”

“…To answer this question, we generated keratinocyte-specific Nfkbiz-deficient mice and analyzed IMQ-induced psoriasis. To assess the effects of a keratinocyte-specific depletion of IκBζ, global IκBζ-deficient mice (8) were analyzed in parallel. Global deletion of IκBζ was studied in inducible-KO mice that received tamoxifen (TAM) for 4 consecutive days to induce Cre recombinase activation.…”

“…Interestingly, it has recently been revealed that expression of IκBζ, encoded by NFKBIZ, is upregulated in psoriatic lesions, while global IκBζ deficiency in mice completely protects against imiquimod-mediated (IMQ-mediated) or IL-36α-mediated psoriasis (7,8). IκBζ belongs to the family of atypical IκBs and constitutes a cofactor of the transcription factor NF-κB that is inducibly expressed in the nucleus, leading to the activation or repression of a selective subset of NF-κB target genes (9)(10)(11)(12).…”

“…Induction of IκBζ and subsequent target gene expression has been investigated in different cell types, such as keratinocytes, macrophages, dendritic cells, and T cells (15). Stimulation of keratinocytes with IL-17A or IL-36 induces IκBζ expression, leading to the induction of several psoriasis-associated target genes, such as Cxcl8, Cxcl2, Defb4, or S100a9 (7,8). In T H 17 cells, IκBζ was found to cooperate with RORγt in regulating the expression of Il17a, Il22, and Tnfa (16).…”