1432 IL-9/IL-9R signaling as a novel regulator of human hair follicle growth and immune privilege

In skin, IL-9 is best known as a key cytokine in contact dermatitis. Yet, we noted that its receptor (IL-9R) was also expressed in the hair follicle (HF) epithelium. Therefore, we asked whether IL-9R-mediated signaling modulated human HF growth and/or immune status. To address this, full-length healthy human scalp HFs were organ-cultured in the presence/absence of recombinant human (rh) IL-9 for six days. Quantitative (immuno-)histomorphometry showed that 5 ng/ml rhIL-9 promoted premature catagen entry, associated with a tendential increase in hair matrix keratinocyte apoptosis and TGFβ2 protein expression. While rhIL-9 did not affect CK15 expression, it significantly decreased the number of CD34+ HF progenitor cells and their CD34 protein expression. Moreover, 5 ng/ml rhIL-9 increased MHC class Ia protein expression in the immune-privileged (IP) anagen HF epithelium, suggesting that IL-9 impairs HF IP. Also, 5 ng/ml rhIL-9 significantly increased the total number of perifollicular mast cells, which regulate hair growth and secrete IL-9, but did not affect their degranulation ex vivo. Instead, IL-9R silencing tendentially prolonged anagen and significantly decreased TGFβ2 and MHC class Ia expression, while CD34 protein expression was upregulated. Our pilot study introduces IL-9/IL-9R signaling as a novel regulator of human HF growth, IP, and proliferation/ maturation of HF-associated mast cells ex vivo. It suggests that IL-9R stimulation inhibits human hair growth and epithelial progenitor cell generation and threatens HF IP. Thus, antagonizing IL-9R signaling, including with IL-9Rγ chain-blocking JAK3 inhibitors, may be beneficial in managing telogen effluvium and androgenetic alopecia, which shows anagen shortening and CD34+progenitor reduction, and in alopecia areata, where HF IP must be restored.