Targeting NF‐κB in macrophages alleviates skin inflammation in a mouse model of psoriasis

Abstract

The pathogenesis and signaling in psoriasis, a chronic inflammatory skin disease, is not well‐understood. We found that, in contrast to skin from healthy subjects or from patients with atopic dermatitis, psoriatic skin exhibits strong activation of transcription factor NF‐κB mainly confined to dermal macrophages, whereas lymphocytes did not show activated NF‐κB. NF‐κB is required for the induction and/or function of many cytokines and aberrant cytokine expression has been proposed as an underlying cause of psoriasis. Therefore, we investigated whether NF‐κB targeting would affect the disease in the transgenic CD18 hypomorphic (CD18hypo) mouse model of psoriasis. When mice with severe psoriasiform lesions were treated systemically or locally with the natural IκB kinase inhibitor acetyl‐11‐keto‐β‐boswellic acid (AKβBA), NF‐κB signaling and the subsequent NF‐κB‐dependent cytokine production (TNF‐α, MCP‐1, IL‐12, and IL‐23) was profoundly suppressed. Additionally, application of the compound led to resolution of the abundant immune cell infiltrates, and reduced the increased proliferation of the keratinocytes. Overall, the AKκBA treatment reconstituted a nearly normal skin phenotype. Thus, NF‐κB signaling is pivotal for the pathogenesis in the CD18hypo mouse model of psoriasis and targeting of NF‐κB in macrophages might provide an effective therapeutic strategy.