The G Protein-Coupled Receptor Kinase 2 (GRK2) Orchestrates Hair Follicle Homeostasis

Tightly regulated cell-cell and cell-niche intercommunications via complex signaling networks are involved in maintaining normal hair follicle (HF) homeostasis, cycling and cell fate determination. However, knowledge of specific mechanisms by which hair loss takes place under pathological situations is still needed. Using a keratinocyte-specific knockout mouse model, we uncover that the G protein-coupled receptor kinase 2 (GRK2) signaling node plays a key role in HF homeostasis. We find that epidermal GRK2 ablation causes early alterations in the hair germ region and altered anagen induction, giving rise to abnormal cyst-like structures. HF-linked cysts display aberrant growth and differentiation patterns as well as lineage infidelity, proliferating steadily overcoming the catagen destructive phase and displaying features of abortive HFs that are unable to fully acquire all the canonical anagen cell layers. Cysts triggered by GRK2 deletion displace the dermal papilla away from the bulge and promote irreversible changes in hair follicle stem cell architecture, eventually leading to bulge destruction and hair loss. Remarkably, epidermal cysts in GRK2 knockout mice are destroyed during aging with features reminiscent of those described in alopecia areata. Our data provide unforeseen roles of GRK2 in epidermal physiology and uncover mechanisms linking dystrophic follicular cysts formation with hair loss, with potential connections to pathogenic processes operating in immune-mediated alopecias.