Reduced TRPC Channel Expression in Psoriatic Keratinocytes Is Associated with Impaired Differentiation and Enhanced Proliferation

Abstract

Psoriasis is a characteristic inflammatory and scaly skin condition with typical histopathological features including increased proliferation and hampered differentiation of keratinocytes. The activation of innate and adaptive inflammatory cellular immune responses is considered to be the main trigger factor of the epidermal changes in psoriatic skin. However, the molecular players that are involved in enhanced proliferation and impaired differentiation of psoriatic keratinocytes are only partly understood. One important factor that regulates differentiation on the cellular level is Ca2+. In normal epidermis, a Ca2+ gradient exists that is disturbed in psoriatic plaques, favoring impaired keratinocyte proliferation. Several TRPC channels such as TRPC1, TRPC4, or TRPC6 are key proteins in the regulation of high [Ca2+]ex induced differentiation. Here, we investigated if TRPC channel function is impaired in psoriasis using calcium imaging, RT-PCR, western blot analysis and immunohistochemical staining of skin biopsies. We demonstrated substantial defects in Ca2+ influx in psoriatic keratinocytes in response to high extracellular Ca2+ levels, associated with a downregulation of all TRPC channels investigated, including TRPC6 channels. As TRPC6 channel activation can partially overcome this Ca2+ entry defect, specific TRPC channel activators may be potential new drug candidates for the topical treatment of psoriasis.

Mechanosensitive ATP release from hemichannels and Ca2+ influx through TRPC6 accelerate wound closure in keratinocytes

“…Hyperforin increases TRPC6 expression levels in the stratum spinosum and stratum granulosum of cultured human skin explants, which results in the terminal differentiation of keratinocytes (Müller et al, 2008). Regarding the expression and function of TRPC6 channels in dermal fibroblasts and epidermal keratinocytes, recent studies have demonstrated that TRPC6-dependent Ca 2+ influx is a prerequisite for wound healing in vivo (Davis et al, 2012) and for topical treatment of psoriasis (Leuner et al, 2011). TRPC6 channels are thought to mediate Ca 2+ influx in response to the activation of G-proteincoupled receptors and stretch stimuli (Spassova et al, 2006;Patel et al, 2010;Nishioka et al, 2011;Shi et al, 2013).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…In psoriatic skin lesions, the expression of TRPC6 is markedly reduced (Leuner et al, 2011). Activation of TRPC5 by hyperforin partially restores the disturbed keratinocyte differentiation in psoriatic lesions (Müller et al, 2008).…”

Defective channels lead to an impaired skin barrier

“…In psoriatic skin, an imbalance in keratinocyte proliferation and differentiation is associated with thickening of the epidermis and a reduced skin barrier function. Psoriatic skin also displays a defect in the epidermal Ca 2+ gradient (Menon and Elias, 1991), which might be partly explained by a reduction in the expression of TRPC1, TRPC4 and TRPC6 observed in psoriatic keratinocytes (Leuner et al, 2011); however, the mechanism for downregulation of these TRPC channels in psoriatic skin is unknown.…”