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.

financial metrics. Cases were stratified by co-surgeon presence, timing, and laterality. RESULTS: 125 cases met inclusion criteria: 49 co-surgeon, 76 single surgeon. Co-surgeon cases demonstrated decreased LOS (2.7 vs. 3.6 days; p = 0.012), operative time in unilateral (317 vs. 423 minutes; p<0.01) and bilateral cases (470 minutes vs. 615 minutes; p<0.01), total charges