Extracellular Granzyme B Promotes Melanocytorrhagy, Melanocyte Senescence and Aberrant Epidermal Differentiation in Vitiligo and Is Therapeutically Targetable
- 1Osaka Metropolitan University
Abstract
Background Vitiligo is an acquired depigmenting disorder characterised by melanocyte loss. While immune responses against melanocytes are implicated in its pathogenesis, melanocyte detachment, melanocyte senescence and aberrant epidermal differentiation are increasingly characterised as additional pathological features. Granzyme B (GzmB), classically recognised as an intracellular effector of perforin-dependent cytotoxicity, is increased in vitiligo lesions; however, its extracellular contribution to vitiligo pathology remains unclear. Objectives To determine whether extracellular GzmB contributes to depigmentation and epidermal pathological features relevant to vitiligo, and to define its cellular source and underlying mechanisms. Methods Human vitiligo skin samples, murine depigmentation models and cultured human epidermal cells were analysed. The functional effects of extracellular GzmB were examined by subcutaneous administration of recombinant GzmB in mice. A rhododendrol (RD)-induced leukoderma model was used to evaluate the disease relevance of GzmB and the therapeutic effect of topical GzmB inhibition with VTI-1002. Results GzmB-positive cells were markedly increased in active vitiligo lesions and were predominantly associated with tryptase-positive cells, with limited co-distribution with CD8 or perforin. Vitiligo lesions also showed melanocyte detachment, increased p16INK4A-positive melanocytes and aberrant keratinocyte differentiation. These pathological features were recapitulated in vivo by extracellular GzmB administration, accompanied by focal depigmentation. In cultured melanocytes, GzmB exerted no cytotoxic effects but reduced attachment strength and induced a senescence-associated phenotype characterised by decreased extracellular matrix- and adhesion-related gene expression, increased p16INK4A level, elevated senescence-associated {beta}-galactosidase activity and activation of transforming growth factor-{beta}/SMAD signalling. In keratinocytes, extracellular GzmB promoted aberrant differentiation associated with activation of p53 signalling. Topical inhibition of GzmB in RD-induced leukoderma attenuated depigmentation progression, melanocyte detachment, melanocyte senescence and abnormal epidermal differentiation. Conclusions Extracellular GzmB promotes depigmentation associated with inducing melanocyte detachment, melanocyte senescence and aberrant keratinocyte differentiation. These findings identify extracellular GzmB as a previously underrecognised pathogenic mediator and potential therapeutic target in vitiligo-associated depigmentation.
Related
- Multilayered extracellular matrix derived scaffolds direct progenitor cell differentiation in vitro and osteochondral-tissue formation in vivo.
- A synthetic xeno-free extracellular matrix surrogate supports robust human induced pluripotent stem cell maintenance and multilineage differentiation
- Tendon-derived injectable bio-instructive gel augments tenogenic differentiation of iMSC-SCX cells and extracellular matrix remodeling
- CD8+ tissue-resident memory T cells are expanded in primary Sjögren's disease and can be therapeutically targeted by CD103 blockade
- BRN2 preserves the melanocyte lineage following ionizing radiation
BibTeX
@misc{diao2026extracellular,
title = {{Extracellular Granzyme B Promotes Melanocytorrhagy, Melanocyte Senescence and Aberrant Epidermal Differentiation in Vitiligo and Is Therapeutically Targetable}},
author = {S. Diao and L. Jin and B. S. Bolla and H. Kuwabiraki and Y. Kuroda and F. Yang and L. Yang and I. Katayama and D. Tsuruta and D. J. Granville and S. Hiroyasu},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.19.752829},
url = {https://www.biorxiv.org/content/10.64898/2026.09.19.752829v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Extracellular Granzyme B Promotes Melanocytorrhagy, Melanocyte Senescence and Aberrant Epidermal Differentiation in Vitiligo and Is Therapeutically Targetable
AU - S. Diao
AU - L. Jin
AU - B. S. Bolla
AU - H. Kuwabiraki
AU - Y. Kuroda
AU - F. Yang
AU - L. Yang
AU - I. Katayama
AU - D. Tsuruta
AU - D. J. Granville
AU - S. Hiroyasu
PY - 2026
DA - 2026/09/19
PB - bioRxiv
DO - 10.64898/2026.09.19.752829
UR - https://www.biorxiv.org/content/10.64898/2026.09.19.752829v1
AB - Background Vitiligo is an acquired depigmenting disorder characterised by melanocyte loss. While immune responses against melanocytes are implicated in its pathogenesis, melanocyte detachment, melanocyte senescence and aberrant epidermal differentiation are increasingly characterised as additional pathological features. Granzyme B (GzmB), classically recognised as an intracellular effector of perforin-dependent cytotoxicity, is increased in vitiligo lesions; however, its extracellular contribution to vitiligo pathology remains unclear. Objectives To determine whether extracellular GzmB contributes to depigmentation and epidermal pathological features relevant to vitiligo, and to define its cellular source and underlying mechanisms. Methods Human vitiligo skin samples, murine depigmentation models and cultured human epidermal cells were analysed. The functional effects of extracellular GzmB were examined by subcutaneous administration of recombinant GzmB in mice. A rhododendrol (RD)-induced leukoderma model was used to evaluate the disease relevance of GzmB and the therapeutic effect of topical GzmB inhibition with VTI-1002. Results GzmB-positive cells were markedly increased in active vitiligo lesions and were predominantly associated with tryptase-positive cells, with limited co-distribution with CD8 or perforin. Vitiligo lesions also showed melanocyte detachment, increased p16INK4A-positive melanocytes and aberrant keratinocyte differentiation. These pathological features were recapitulated in vivo by extracellular GzmB administration, accompanied by focal depigmentation. In cultured melanocytes, GzmB exerted no cytotoxic effects but reduced attachment strength and induced a senescence-associated phenotype characterised by decreased extracellular matrix- and adhesion-related gene expression, increased p16INK4A level, elevated senescence-associated {beta}-galactosidase activity and activation of transforming growth factor-{beta}/SMAD signalling. In keratinocytes, extracellular GzmB promoted aberrant differentiation associated with activation of p53 signalling. Topical inhibition of GzmB in RD-induced leukoderma attenuated depigmentation progression, melanocyte detachment, melanocyte senescence and abnormal epidermal differentiation. Conclusions Extracellular GzmB promotes depigmentation associated with inducing melanocyte detachment, melanocyte senescence and aberrant keratinocyte differentiation. These findings identify extracellular GzmB as a previously underrecognised pathogenic mediator and potential therapeutic target in vitiligo-associated depigmentation.
ER -