Nrf2 Involvement in Chemical-Induced Skin Innate Immunity

Abstract

Exposure to certain chemicals disturbs skin homeostasis. In particular, protein-reactive chemical contact sensitizers trigger an inflammatory immune response resulting in eczema and allergic contact dermatitis. Chemical sensitizers activate innate immune cells which orchestrate the skin immune response. This involves oxidative and inflammatory pathways. In parallel, the Nrf2/Keap1 pathway, a major ubiquitous regulator of cellular oxidative and electrophilic stress is activated in the different skin innate immune cells including epidermal Langerhans cells and dermal dendritic cells, but also in keratinocytes. In this context, Nrf2 shows a strong protective capacity through the downregulation of both the oxidative stress and inflammatory pathways. In this review we highlight the important role of Nrf2 in the control of the innate immune response of the skin to chemical sensitizers.

Keywords: Nrf2; contact sensitizers; innate immunity; skin cells; xenoinflammation.

Figure 1

Crosstalk between Nrf2 and NF-κB transcription factors. Nrf2 and NF-κB related pathways are sensitive to oxidative stress that induces their activation. Nrf2 antagonizes NF-κB activation through IKK proteasomal activation and HO-1 activity end-products. In parallel, NF-κB downregulates Nrf2 via p65-mediated CBP deprivation as well as p65-induced Keap1 nuclear translocation. Nrf2 and NF-κB are regulated antagonistically: (i) if Nrf2 predominates, it decreases inflammation and oxidative stress through activation of antioxidant enzymes; (ii) when NF-κB predominates, it leads to pro-inflammatory mediators secretion and maintains the oxidative stress.

Figure 2

Role of Nrf2 in the principal skin innate immune cells including keratinocytes, dendritic cells, and macrophages.

Figure 3

Nrf2 stabilization and anti-inflammatory effects following immune cell exposure to chemical sensitizers. In homeostatic conditions, Nrf2 is continuously repressed by the Keap1-Cul3 complex and ubiquitinylated. Exposure to chemical sensitizers (CS) activates the Nrf2/Keap1 pathway through different ways: (1) ROS-mediated activation resulting from CS irritancy and degradation of extracellular matrix (ECM), (2) direct chemical modification of Keap1, (3) TLR-dependent activation. Thus, modifications on Keap1 lead to Nrf2 stabilization and phosphorylation. Nrf2 translocates then to the nucleus where it binds to ARE sequences promoting the transcription of antioxidant genes and inhibiting the transcriptional activity of several genes encoding pro-inflammatory cytokines.