CD271 orchestrates skin structure, differentiation, and inflammation via PI3K/Akt and PKCα/ERK pathways

The involvement of the neurotrophin network in pathological skin conditions by their common neurotrophin receptor CD271 has become recently evident. CD271 mediates various cellular responses in keratinocytes, and in vitro analysis shows that it is implicated in human interfollicular keratinocyte stem cells-transient amplifying cell switch. However, no in vivo models are available to dissect the complexity of these mechanisms, including the effect on the inflammatory response. We characterize novel mouse models, CD271cKO and CD271ciKO, where CD271 is conditionally absent in keratinocytes during development or after topical induction, respectively. We identified substantial skin changes by histology, transcriptomic, and molecular analysis, including epidermal hyperproliferation and “activated” keratinocyte signature, linked to PI3K/Akt and mitogenic pathways. KO keratinocyte displays upregulation of Ki67, PCNA, KRT5, KRT6, and P-ERK, as well as IL1α, IL8, and TGFβ. KO skin showed significant recruitment of CD45, CD4, and CD8+ cells, and release of inflammatory cytokines . Overall, our data defines CD271 as a crucial regulator of skin homeostasis and inflammation. Our models represent exceptionally useful tools for characterization and, subsequently, development of therapies for skin conditions characterized by modulation of keratinocyte homeostatic balance.