Abstract
The skin represents an indispensable barrier between the organism and the environment and is the first line of defense against exogenous insults. The transcription factor NRF2 is a central regulator of cytoprotection and stress resistance. NRF2 is activated in response to oxidative stress by reactive oxygen species (ROS) and electrophiles. These electrophiles oxidize specific cysteine residues of the NRF2 inhibitor KEAP1, leading to KEAP1 inactivation and, subsequently, NRF2 activation. As oxidative stress is associated with inflammation, the NRF2 pathway plays important roles in the pathogenesis of common inflammatory diseases and cancer in many tissues and organs, including the skin. The electrophile and NRF2 activator dimethyl fumarate (DMF) is an established and efficient drug for patients suffering from the common inflammatory skin disease psoriasis and the neuro-inflammatory disease multiple sclerosis (MS). In this review, we discuss possible molecular mechanisms underlying the therapeutic activity of DMF and other NRF2 activators. Recent evidence suggests that electrophiles not only activate NRF2, but also target other inflammation-associated pathways including the transcription factor NF-κB and the multi-protein complexes termed inflammasomes. Inflammasomes are central regulators of inflammation and are involved in many inflammatory conditions. Most importantly, the NRF2 and inflammasome pathways are connected at different levels, mainly antagonistically.
Highlights
The skin is the largest organ of the human body and represents its outermost barrier, which is in permanent contact with the environment [1]
The electrophile dimethyl fumarate (DMF) is used as a rather safe and well established drug for the treatment of patients suffering from the common inflammatory skin disease psoriasis [20] or from the neurological disorder relapsing-remitting multiple sclerosis (RRMS) [54,55]
This is well known for reversible modifications of cysteine residues by oxidized glutathione under conditions characterized by oxidative stress, and reactive oxygen species (ROS) associated with inflammatory conditions [27,28,29]
Summary
The skin is the largest organ of the human body and represents its outermost barrier, which is in permanent contact with the environment [1]. Epidermal keratinocytes form the outer structural barrier of the skin, and express, in a constitutive or inducible manner, molecules, peptides and proteins which are actively involved in different defense and protective mechanisms [2]. Inflammation is induced, among other things, upon the activation of inflammasomes, which are multi-protein complexes expressed by immune cells, such as macrophages and dendritic cells, and by keratinocytes [9,10]. Inflammasomes detect many different stress factors and induce inflammation upon the regulation of activation and secretion of the proinflammatory cytokines (pro)interleukin(IL)-1β and -18. The transcription factor NF-κB (nuclear factor κ light chain enhancer of activated B cells) plays a central role in homeostasis and inflammation in the skin [2,11,12] and participates in inflammasome and NRF2 regulation in a complex manner [13,14]. We discuss the different molecular mechanisms, which might underlie the pharmacological activity of DMF and other electrophiles in psoriasis, RRMS and other inflammatory (skin) diseases
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