Immunometabolism in the pathogenesis of vitiligo

Abstract

Vitiligo is a common depigmenting skin disorder characterized by the selective loss of melanocytes. Autoimmunity, genetic, environmental, and biochemical etiology have been proposed in vitiligo pathogenesis. However, the exact molecular mechanisms of vitiligo development and progression are unclear, particularly for immunometabolism. Sporadic studies have suggested mitochondrial dysfunction, enhanced oxidative stress, and specific defects in other metabolic pathways can promote dysregulation of innate and adaptive immune responses in vitiligo. These abnormalities appear to be driven by genetic and epigenetic factors modulated by stochastic events. In addition, glucose and lipid abnormalities in metabolism have been associated with vitiligo. Specific skin cell populations are also involved in the critical role of dysregulation of metabolic pathways, including melanocytes, keratinocytes, and tissue-resident memory T cells in vitiligo pathogenesis. Novel therapeutic treatments are also raised based on the abnormalities of immunometabolism. This review summarizes the current knowledge on immunometabolism reprogramming in the pathogenesis of vitiligo and novel treatment options.

Keywords: glucose metabolism; immunometabolism; immunotherapy; lipid metabolism; oxidative stress; vitiligo.

Figure 1

Abnormal metabolic processes in melanocytes during oxidative stress. Oxidative stress triggered abnormal glycolipid metabolism within melanocytes, disrupting metabolic pathways. Melanocytes with mitochondrial disorders, abnormal melanin biosynthesis, and dysregulated metabolic pathway produce abnormal ROS, exacerbating oxidative stress. The orange-boxed portion of the figure shows outlier segments, as reported in recent literature. In addition, melanocytes interact with different immune cells in innate and adaptive immunity, leading to melanocyte loss ultimately. ARE, antioxidant response element; CAT, catalase; HO-1, heme oxygenase-1; Nrf2, nuclear factor E2-related factor 2; ROS, reactive oxygen species; SOD, superoxide dismutase; GLUTs, glucose transporters; PDC, pyruvate dehydrogenase complex; PDKs, pyruvate dehydrogenase kinase; ETC, electron transport chain; FAO, fatty acid oxidation; G-6-PD, glucose-6-phosphate dehydrogenase; UPR, unfolded protein response; DAMPs, damage-associated molecular patterns; NK, natural killer cells; ILC, innate lymphoid cells; IFN-γ, inteferon-γ; CXCL9, C-X-C motif chemokine ligand 9; CXCL10, C-X-C motif chemokine ligand 10; CXCL16, C-X-C motif chemokine ligand 16.

Figure 2

Vitiligo immunometabolism promising targets. CD8⁺ T cells in vitiligo lesions can produce a variety of cytokines, including IFN-γ. Elevated levels of IFN-γ disrupt glucose metabolism and promote melanocyte apoptosis. IFN-γ binds with IFNgR, activates the JAK-STAT pathway, and leads to the secretion of CXCL9 and CXCL10 in the skin. JAK-STAT signaling pathway activation plays a vital role in various metabolic disorders and can be treated with JAK inhibitors (e.g. ruxolitinib) acting on JAK1 and JAK2. CXCL9 promotes massive recruitment of melanocyte-specific CD8⁺ T cells to the skin via the cognate receptor CXCR3, while CXCL10 promotes their localization within the epidermis and their effector functions, which increases inflammation through a positive feedback loop. Activation of CXCR3B by CXCL10 induces apoptosis of melanocytes. However, depleting antibodies acting on CXCR3 could reduce the number of C8+ T cells, thereby reversing the disease. In addition, flavonoids act by activating the Nrf2/ARE signaling pathway and inhibiting NFκB activation by reducing the extent of oxidative stress in melanocytes. Established vitiligo lesions are maintained by melanocyte-reactive T_RM cells that maintain longevity in the skin via IL-15-dependent survival signals. T_RM is linked to lipid metabolism due to their reliance on exogenous free fatty acid (FFA) uptake to maintain their residence in the skin. The use of antibodies against CD122, the β subunit of the IL-15 receptor, in a mouse model of vitiligo effectively inhibits T_RM production. IL-15 and its receptor may be a target for vitiligo treatment. CXCR3, C-X-C motif chemokine receptor 3; CXCL9/10, C-X-C motif chemokine ligand 9/10; IFN-γ, inteferon-γ; IL-15, interleukin-15; IFNgR, inteferon-gamma receptor; T_RM, resident memory T cells; TCR, T cell receptor; HLA, human leukocyte antigen; STAT1, signal transducer and activator of transcription protein 1; JAK, janus kinases.