The protease-activated receptor-2 upregulates keratinocyte phagocytosis

Abstract

The protease-activated receptor-2 (PAR-2) belongs to the family of seven transmembrane domain receptors, which are activated by the specific enzymatic cleavage of their extracellular amino termini. Synthetic peptides corresponding to the tethered ligand domain (SLIGRL in mouse, SLIGKV in human) can activate PAR-2 without the need for receptor cleavage. PAR-2 activation is involved in cell growth, differentiation and inflammatory processes, and was shown to affect melanin and melanosome ingestion by human keratinocytes. Data presented here suggest that PAR-2 activation may regulate human keratinocyte phagocytosis. PAR-2 activation by trypsin, SLIGRL or SLIGKV increased the ability of keratinocytes to ingest fluorescently labeled microspheres or E. coli K-12 bioparticles. This PAR-2 mediated increase in keratinocyte phagocytic capability correlated with an increase in actin polymerization and *-actinin reorganization, cell surface morphological changes and increased soluble protease activity. Moreover, addition of serine protease inhibitors downmodulated both the constitutive and the PAR-2 mediated increases in phagocytosis, suggesting that serine proteases mediate this functional activity in keratinocytes. PAR-2 involvement in keratinocyte phagocytosis is a novel function for this receptor.

Melanocore uptake by keratinocytes occurs through phagocytosis and involves protease‐activated receptor‐2 internalization

“…The protease‐activated receptor‐2 (PAR‐2) is one of the few molecular players described to control melanin transfer both in vivo and in vitro. Moreover, it is known that PAR‐2 stimulation leads to the enhancement of melanin transfer, as well as keratinocyte phagocytosis 13–17 . In addition, we showed that PAR‐2 regulates the uptake of melanocores, but not melanosomes 18 .…”

“…Moreover, it is known that PAR-2 stimulation leads to the enhancement of melanin transfer, as well as keratinocyte phagocytosis. [13][14][15][16][17] In addition, we showed that PAR-2 regulates the uptake of melanocores, but not melanosomes. 18 Nonetheless, it is not clear what is the route followed by melanin to enter keratinocytes.…”

“…The major difference is that macropinocytosis is a general process performed by most cells to take up nutrients from the extracellular milieu, while phagocytosis is mainly performed by specialized cells and is usually specific for the particles engulfed as it is receptor‐mediated. Nevertheless, keratinocytes were shown to possess phagocytic ability 16,40,41 . To characterize the endocytic route followed by melanin, we silenced Rac1, Cdc42, RhoA or CtBP1/BARS in XB2 keratinocytes (Figure S2), before incubating them for 24 h with melanocores or melanosomes.…”

Melanin Synthesis Inhibitors from Balanophora fungosa

“…[2][3][4][5][6] Keratinocytes ingest the synthesized melanin through the melanocyte dendrite, following an increase of protease-activated receptor 2 (PAR-2) activation. [7][8][9][10][11] Trypsin and mast cell tryptase are known to be activators of PAR-2. 12, 13 Accordingly, the inhibitors of these enzymes (tyrosinase, trypsin, and tryptase) have the potential to become hypopigment agents, which prevent the overproduction of melanin in the skin.…”

“…Dendritic cells known as melanocytes, which are located at basal lamina, are responsible for producing melanin in the skin . Tyrosinase (EC 1.14.18.1) synthesized in the melanocytes plays an important role in melanin synthesis, such as the hydroxylation of l -tyrosine to 3,4-dihydroxy- l -phenylalanine ( l -DOPA), oxidation of l -DOPA to dopaquinone, and oxidation of 5,6-dihydroxyindole to indolequinone. − Keratinocytes ingest the synthesized melanin through the melanocyte dendrite, following an increase of protease-activated receptor 2 (PAR-2) activation. − Trypsin and mast cell tryptase are known to be activators of PAR-2. , Accordingly, the inhibitors of these enzymes (tyrosinase, trypsin, and tryptase) have the potential to become hypopigment agents, which prevent the overproduction of melanin in the skin. − …”