Misbalanced CXCL12 and CCL5 Chemotactic Signals in Vitiligo Onset and Progression

Abstract

Generalized nonsegmental vitiligo is often associated with the activation of melanocyte-specific autoimmunity. Because chemokines play an important role in the maintenance of immune responses, we examined chemotactic signatures in cultured vitiligo melanocytes and skin samples of early (≤2 months) and advanced (≥6 months) vitiligo. Analysis showed that melanocytes in early lesions have altered expression of several chemotaxis-associated molecules, including elevated secretion of CXCL12 and CCL5. Higher levels of these chemokines coincided with prominent infiltration of the skin with antigen presenting cells (APCs) and T cells. Most of the intralesional APCs expressed the CD86 maturation marker and co-localized with T cells, particularly in early vitiligo lesions. These observations were confirmed by in vivo animal studies showing preferential recruitment of APCs and T cells to CXCL12- and CCL5-expressing transplanted melanocytes, immunotargeting of the chemokine-positive cells, continuous loss of the pigment-producing cells from the epidermis, and development of vitiligo-like lesions. Taken together, our studies show that melanocyte-derived CXCL12 and CCL5 support APC and T-cell recruitment, antigen acquisition, and T-cell activation in early vitiligo and reinforce the role of melanocyte-derived CXCL12 and CCL5 in activation of melanocyte-specific immunity and suggest inhibition of these chemotactic axes as a strategy for vitiligo stabilization.

Alterations of CXCL12 in Serum of Patients with Vitiligo

“…In conclusion, these data support the findings of Rezk et al (2017) for a role of CXCL12 in the pathogenesis of vitiligo. Especially, its capacity to predict future disease progression in stable patients is promising.…”

Pro-Inflammatory Chemokines and Cytokines Dominate the Blister Fluid Molecular Signature in Patients with Epidermolysis Bullosa and Affect Leukocyte and Stem Cell Migration

“…Yet, CXCL12 -CXCR4 chemotactic axis was mostly associated with dissemination of cancers to the lymph node, bone, lung, brain, and liver (Sun et al, 2010, Teicher and Fricker, 2010). In the skin, CXCL12 expression was associated with skin-infiltrating dendritic cells, pericytes, endothelial cells and fibroblasts (Avniel et al, 2006, Rezk et al, 2017), as well as with emigration of dendritic cells from the cutaneous tissue (Kabashima et al, 2007). In fact, data presented by Ujiie et al also demonstrate that CXCL12 expression in the EB-affected skin is mostly associated with skin infiltrating cell.…”

CXCL12 as a Predictor of Vitiligo Activity and Disease Progression

“…The answer to this question may lie within vitiligo-affected lesional and perilesional skin. We reported that vitiligo melanocytes express and secrete higher levels of CXCL12 (Rezk et al, 2017). Because melanocytes represent a small population of cells in the cutaneous tissue, it is unlikely that melanocyte-derived CXCL12 would have an impact on its systemic level.…”

“…Recently, we showed that elevated expression of CCL5 and CXCL12 in cutaneous melanocytes is associated with vitiligo onset and progression (Rezk et al, 2017). Extending this work to the systemic compartment, in the letter titled "Alterations of CXCL12 in Serum of Vitiligo Patients" Speeckaert and coauthors (2017) assessed CXCL12 level in the sera samples from nonsegmental vitiligo patients and correlated it with disease activity.…”