Allergic Skin Inflammation Induced by Chemical Sensitizers Is Controlled by the Transcription Factor Nrf2

Abstract

Allergic contact dermatitis (ACD) is induced by low-molecular weight electrophilic chemicals and metal ions. Chemical contact sensitizers trigger reactive oxygen species production and provoke electrophilic stress, leading to the accumulation of the transcription factor nuclear-related factor 2 (Nrf2) in innate immune cell types. The objective of this work was to identify the role of Nrf2 in the regulation of ACD. We used the local lymph node assay (LLNA) and the mouse ear swelling test (MEST) to study the role of Nrf2 in both the sensitization and elicitation phase in nrf2 knockout (nrf2(-/-)) and wild-type (nrf2(+/+)) mice. Five chemicals were used: two compounds known to react with cysteine residues, 2,4-dinitrochlorobenzene (DNCB) and cinnamaldehyde (CinA); one sensitizer known to exhibit mixed reactivity to cysteine and lysine residues, isophorone diisocyanate; and one reacting specifically with lysine residues, trimellitic anhydride and croton oil, a well-known irritant. In the MEST assay, DNCB (1 and 2%) induced a significant increase in ear thickness in nrf2(-/-) compared with nrf2(+/+) mice, suggesting a role for Nrf2 in the control of the inflammatory process. When DNCB was used at 0.25 and 0.5% or when mice were treated with CinA, inflammation was found only in nrf2(-/-) mice. In the LLNA, all chemical sensitizers induced an increase of lymphocyte proliferation in nrf2(-/-) compared with nrf2(+/+) mice for the same chemical concentration. These results reveal an important role for Nrf2 in controlling ACD and lymphocyte proliferation in response to sensitizers.

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

“…For example, genetic or pharmacological activation of Nrf2 in keratinocytes caused skin inflammation, hyperkeratosis, and sebaceous gland enlargement (4,5). Furthermore, various NRF2-activating compounds are skin sensitizers (22,23), and recent studies suggest that Nrf2 can promote atherosclerosis in mice (24). Finally, activation of NRF2 occurs in different types of human cancers, which promotes proliferation of cancer cells and their survival under stress conditions (2).…”

The nuclear factor-erythroid 2-related factor/heme oxygenase-1 axis is critical for the inflammatory features of type 2 diabetes–associated osteoarthritis

“…. Moreover, experiments were also performed using Nrf-2 knockout (Nrf-2 −/− ) (61) mice generated from inbred Nrf-2 heterozygous mice on a C57BL/6J background, as described by El Ali et al (62). The mice were housed in a pathogen free facility and were handled in accordance with the principles and procedures outlined in Council Directive 86/609/EEC.…”

Mechanistic Understanding of Contact Allergy

“…HA fragments can then activate these TLRs. In addition, they cause oxidative stress and activation of the antioxidant phase II response due to their induction of reactive oxygen species (ROS) [19,20]. All of these contact allergens activate the NLRP3 inflammasome.…”