Insights into the context-dependent immunological roles of the CXCL12–CXCR4 axis in alopecia

The CXCL12–CXCR4 axis plays a dual role in hair follicle biology, promoting hair regeneration under normal conditions but driving hair loss in alopecia, particularly in androgenetic alopecia (AGA) and alopecia areata (AA). In these conditions, CXCL12–CXCR4 signaling contributes to a fibroimmune microenvironment that leads to dermal fibrosis, chronic inflammation, and hair follicle miniaturization. The expression of CXCR4 is mainly found on pro-inflammatory macrophages and dermal papilla cells in diseased scalps, linking these cells to hair follicle damage. While regulatory T cells (Tregs) express CXCR4, their role in hair growth is minor compared to the pathological signals in alopecia. Therapeutically, blocking the CXCL12–CXCR4 axis has shown promise in reversing fibrosis, reducing immune cell accumulation, restoring dermal papilla cell function, and stimulating hair regrowth in AGA and AA models. The study highlights the importance of understanding the cellular sources and pathogenic roles of CXCL12–CXCR4 signaling in alopecia and the potential of targeting this axis as a treatment strategy.