LPA induces keratinocyte differentiation and promotes skin barrier function through the LPAR1/LPAR5-RHO-ROCK-SRF axis

Abstract

The skin barrier protects our body from water loss, allergens and pathogens. Profilaggrin (proFLG) is produced by differentiated keratinocytes and is processed into FLG monomers. These monomers crosslink keratin filaments and are also decomposed to natural moisturizing factors in the stratum corneum for skin hydration and barrier function. Deficits in FLG expression impair skin barrier function and underlie skin diseases such as dry skin and atopic dermatitis (AD). However, intrinsic factors that regulate FLG expression and their mechanism of action remain unknown. Here, we show that lysophosphatidic acid (LPA) induces FLG expression in human keratinocytes via the LPAR1 and LPAR5 receptors and the downstream RHO-ROCK-SRF pathway. Comprehensive gene profiling analysis further revealed that LPA not only induces FLG expression but also facilitates keratinocyte differentiation. Moreover, LPA treatment significantly upregulated FLG production in a three-dimensional culture model of human skin, and promoted barrier function in mouse skin in vivo. Thus, our work demonstrates a previously unsuspected role for LPA and its downstream signaling in the maintenance of skin homeostasis, which may serve as a novel therapeutic target for skin barrier dysfunction.