LPA Induces Keratinocyte Differentiation and Promotes Skin Barrier Function through the LPAR1/LPAR5-RHO-ROCK-SRF Axis

Abstract

The skin barrier protects the body from water loss, allergens, and pathogens. Profilaggrin is produced by differentiated keratinocytes and is processed into filaggrin monomers. These monomers cross-link 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. However, intrinsic factors that regulate FLG expression and their mechanisms of action remain unknown. Here, we show that lysophosphatidic acid induces FLG expression in human keratinocytes via the LPAR1 and LPAR5 receptors and the downstream RHO-ROCK-SRF pathway. Comprehensive gene profiling analysis further showed that lysophosphatidic acid not only induces FLG expression but also facilitates keratinocyte differentiation. Moreover, lysophosphatidic acid treatment significantly up-regulated FLG production in a three-dimensional culture model of human skin and promoted barrier function in mouse skin in vivo. Thus, our work shows a previously unsuspected role for lysophosphatidic acid and its downstream signaling in the maintenance of skin homeostasis, which may serve as a novel therapeutic target for skin barrier dysfunction.

Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages

“…Although we focused on the impact of LPA 5 on macrophage modulation in psoriasis, LPA 5 could also contribute to psoriasis lesions by modulating functions of other psoriasis-associated cell types, such as keratinocyte [46,47]. Topical LPA application can increase keratinocytes proliferation and epidermal thickness [48] and ameliorate skin barrier function through LPA 1 /LPA 5 [17]. Sumitomo et al [17] have examined filaggrin expression to assess keratinocyte differentiation and skin barrier function because filaggrin was associated with skin diseases such as dry skin and atopic dermatitis.…”

“…Topical LPA application can increase keratinocytes proliferation and epidermal thickness [48] and ameliorate skin barrier function through LPA 1 /LPA 5 [17]. Sumitomo et al [17] have examined filaggrin expression to assess keratinocyte differentiation and skin barrier function because filaggrin was associated with skin diseases such as dry skin and atopic dermatitis. Even though loss-of-function mutations in the gene of filaggrin are not associated with psoriasis [38], it is sure that LPA 5 -mediated LPA signaling influences keratinocyte biology [17] and keratinocytes are the major cell type to contribute to psoriasis lesions [46,47].…”

“…Sumitomo et al [17] have examined filaggrin expression to assess keratinocyte differentiation and skin barrier function because filaggrin was associated with skin diseases such as dry skin and atopic dermatitis. Even though loss-of-function mutations in the gene of filaggrin are not associated with psoriasis [38], it is sure that LPA 5 -mediated LPA signaling influences keratinocyte biology [17] and keratinocytes are the major cell type to contribute to psoriasis lesions [46,47]. Therefore, roles of LPA 5 in psoriasis could be additionally associated with regulation of keratinocyte biology.…”

“…Furthermore, it has been shown that LPA 5 is highly expressed in dorsal root ganglion and its signaling is involved in LPA-induced itch in mice [13,16]. LPA 5 was reported to be highly expressed in normal human epidermal keratinocytes [17]. It has also been suggested as a putative regulator of keratinocyte differentiation and skin barrier function [17], both of which are regarded as important events in psoriasis [4].…”

“…LPA 5 was reported to be highly expressed in normal human epidermal keratinocytes [17]. It has also been suggested as a putative regulator of keratinocyte differentiation and skin barrier function [17], both of which are regarded as important events in psoriasis [4]. However, whether LPA 5 contributes to tissue injury of psoriasis remains unclear.…”