Epidermal Growth Factor Modulates Palmitic Acid-Induced Inflammatory and Lipid Signaling Pathways in SZ95 Sebocytes

Abstract

Epidermal growth factor (EGF) acts as a paracrine and autocrine mediator of cell proliferation and differentiation in various types of epithelial cells, such as sebocytes, which produce the lipid-rich sebum to moisturize the skin. However, sebum lipids via direct contact and by penetrating through the epidermis may have regulatory roles on epidermal and dermal cells as well. As EGF receptor (EGFR) is expressed throughout the proliferating and the lipid-producing layers of sebaceous glands (SGs) in healthy and acne-involved skin, we investigated the effect of EGF on SZ95 sebocytes and how it may alter the changes induced by palmitic acid (PA), a major sebum component with bioactive roles. We found that EGF is not only a potent stimulator of sebocyte proliferation, but also induces the secretion of interleukin (IL)6 and down-regulates the expression of genes involved in steroid and retinoid metabolism. Importantly, when applied in combination with PA, the PA-induced lipid accumulation was decreased and the cells secreted increased IL6 levels. Functional clustering of the differentially regulated genes in SZ95 sebocytes treated with EGF, PA or co-treated with EGF+PA further confirmed that EGF may be a potent inducer of hyperproliferative/inflammatory pathways (IL1 signaling), an effect being more pronounced in the presence of PA. However, while a group of inflammatory genes was up-regulated significantly in EGF+PA co-treated sebocytes, PA treatment in the absence of EGF, regulated genes only related to cell homeostasis. Meta-analysis of the gene expression profiles of whole acne tissue samples and EGF- and EGF+PA -treated SZ95 sebocytes showed that the EGF+PA co-activation of sebocytes may also have implications in disease. Altogether, our results reveal that PA-induced lipid accumulation and inflammation can be modulated by EGF in sebocytes, which also highlights the need for system biological approaches to better understand sebaceous (immuno)biology.

Sebaceous immunobiology - skin homeostasis, pathophysiology, coordination of innate immunity and inflammatory response and disease associations

“…Starting from previous observation, Törőcsik et al. ( 20 ) cultivated SZ95 sebocytes with palmitic acid plus EGF, the cells lipid accumulation was decreased and IL6 level was increased. Compared the gene expression profile of SZ95 sebocytes cultured without EGF supplementation, the down-regulated 218 transcripts formed clusters related to steroid, retinoid and lipid metabolism, and to epidermal differentiation.…”

“…Linoleic acid had also an anti-inflammatory effect in P. acnes -activated monocyte-derived macrophages by inhibiting the secretion of IL1β ( 19 ). Delivering further important findings on the immune modulatory effects of the secreted sebum lipids on sebocytes themselves, palmitic acid may be a potent pro-inflammatory stimulus also for sebocytes under certain conditions such as the presence of epidermal growth factor (EGF) ( 20 , 145 , 146 ). Sebocyte-derived proteins and lipids may modify the microbiota through nutritional as well as anti-microbial actions.…”

“…Moreover, supported by widely used human models ( 14 , 15 ), evidence has lately been provided that sebocytes overtake the coordination of cellular communication inside the skin and are occasionally able to substitute professional inflammatory cells in the induction of innate immunity responses ( 2 , 4 ). The - at least partial - elucidation of sebaceous hormone- and lipid-induced inflammation and its regulation ( 16 – 20 ) has widened our understanding for the involvement of the SG in skin inflammatory processes over the borders of acne, including psoriasis, atopic dermatitis, hidradenitis suppurativa and skin aging ( 2 , 21 – 29 ), and has opened new signaling options for treatment of inflammatory skin and SG diseases ( 30 , 31 ).…”

Multiorgan‐on‐a‐chip for realization of gut‐skin axis

“…We examined the effect of adding free fatty acid, PA, to the gut epithelium, in either intact or impaired condition. PA was chosen based on previous studies that PA can cause inflammation in the gut epithelium as well as skin barrier, suggesting involvement of this molecule in the gut and skin‐related inflammatory diseases (Gori et al, 2020; Torocsik et al, 2021). We added PA to the gut, with or without LPS or DSS, and examined the viability of skin cells (dermal fibroblasts and keratinocytes) by using CCK‐8 (Figure 5a).…”

Clinical and Histological Effects of Topical Epidermal Growth Factor on Acne and Acne Scars

“…Thus, rhEGF prevented the excessive destruction of the extracellular matrix and improved the atrophic scars. Further study on the expression location of molecular markers is needed to compare with previously reported in vitro findings for the effect of EGF on sebocytes and to elucidate the mechanism of EGFO on acne and acne scars [43].…”