Alopecia Areata: A Review of the Role of Oxidative Stress, Possible Biomarkers, and Potential Novel Therapeutic Approaches

Abstract

Alopecia areata (AA) is a dermatological condition characterized by non-scarring hair loss. Exact etiopathogenesis of AA is still unknown although it is known that several factors contribute to the collapse of the hair-follicle (HF)-immune-privileged (IP) site. Oxidative stress (OS) plays an important role in skin diseases. The aim of this review was to clarify the role of OS in AA pathogenesis and diagnosis, and to discuss potential treatment options. Oxidative-stress markers are altered in serum and skin samples of patients with AA, confirming a general pro-oxidative status in patients with AA. OS induces MHC class I chain-related A (MICA) expression in HF keratinocytes that activates the receptor NKG2D, expressed in NK cells and CD8+ T cytotoxic cells leading to destabilization of the HF immune-privileged site through the production of IFN-γ that stimulates JAK1 and JAK2 pathways. OS also activates the KEAP1-NRF2 pathway, an antioxidant system that contributes to skin homeostasis. In addition, a decrease of ATG5 and LC3B in the hair matrix and an increase in p62 levels indicates a reduction of intrafollicular autophagy during the evolution of AA. Potential biomarkers of OS in AA could be: malondialdehyde (MDA), advanced glycation end-products (AGEs), and ischemic-modified albumin (IMA). JAK inhibitors are the new frontier in treatment of AA and the use of nutraceuticals that modulate the OS balance, in combination with standard treatments, represent promising therapeutic tools.

Keywords: JAK inhibitors; alopecia areata; autophagy; biomarkers; nutraceuticals; oxidative stress.

Figure 1

Summary of the main markers related to oxidative stress (OS) principal molecular targets: lipidis, DNA, proteins, and IMA. Abbreviations: 8oxodG, 7,8-dihydroxy-8-oxo-2′-deoxyguanosine; AGEs, advanced glycation end-products; ALEs, advanced lipoxigenation end-products; AOPP advanced oxidation protein-products; F2-IsoPs, F2-isoprostanes; HNE, 4-hydroxy-2-nonenal; IMA, ischemia-modified albumin; MDA, malondialdehyde; TBARS, thiobarbituric acid reactive substances.

Figure 2

Oxidative stress (OS) induces the production of autoantigens and the expression of NKG2DL and MHCI in keratinocytes and melanocytes. CD8+ cells expressing NKG2D become effector cells by binding to the NKG2D receptor. CD8+ cells produce IL-2 and IL-15, granzyme b (GZM), and interferon gamma (INF-γ). INF-γ activates the JAK-STAT signaling pathway which can induce further abnormal expression.