PT  - JOURNAL ARTICLE
AU  - Hyeung Ju Park
AU  - Raghu P. Kataru
AU  - Jinyeon Shin
AU  - Gabriela D. García Nores
AU  - Elizabeth M. Encarnacion
AU  - Mark G. Klang
AU  - Elyn Riedel
AU  - Michelle Coriddi
AU  - Joseph H. Dayan
AU  - Babak J. Mehrara
TI  - Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema
AID  - 10.1101/2023.01.20.524936
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.01.20.524936
4099  - http://biorxiv.org/content/early/2023/01/21/2023.01.20.524936.short
4100  - http://biorxiv.org/content/early/2023/01/21/2023.01.20.524936.full
AB  - Epidermal changes are histological hallmarks of secondary lymphedema, but it is unknown if keratinocytes contribute to its pathophysiology. Using clinical lymphedema specimens and mouse models, we show that keratinocytes play a primary role in lymphedema development by producing T-helper 2 (Th2) -inducing cytokines. Specifically, we find that keratinocyte proliferation and expression of protease-activated receptor 2 (PAR2) are early responses following lymphatic injury and regulate the expression of Th2-inducing cytokines, migration of Langerhans cells, and skin infiltration of Th2-differentiated T cells. Furthermore, inhibition of PAR2 activation with a small molecule inhibitor or the proliferation inhibitor teriflunomide (TF) prevents activation of keratinocytes stimulated with lymphedema fluid. Finally, topical TF is highly effective for decreasing swelling, fibrosis, and inflammation in a preclinical mouse model. Our findings suggest that lymphedema is a chronic inflammatory skin disease, and topically targeting keratinocyte activation may be a clinically effective therapy for this condition.Competing Interest StatementThe authors have declared no competing interest.