CARD14 Expression in Dermal Endothelial Cells in Psoriasis

Abstract

Mutations in the caspase recruitment domain, family member 14 (CARD14) gene have recently been described in psoriasis patients, and explain the psoriasis susceptibility locus 2 (PSORS2). CARD14 is a scaffolding protein that regulates NF-κB activation, and psoriasis-associated CARD14 mutations lead to enhanced NF-κB signaling. CARD14 is expressed mainly in epidermal keratinocytes, but also in unidentified dermal cells. In this manuscript, the identity of the dermal cell types expressing CARD14, as well the potential functional consequence of overactive CARD14 in these dermal cell types, was determined. Using two-color immunofluorescence, dermal CARD14 did not co-localize with T-cells, dendritic cells, or macrophages. However, dermal CARD14 did highly co-localize with CD31+ endothelial cells (ECs). CARD14 was also expressed non-dermal endothelial cells, such as aortic endothelial cells, which may indicate a role of CARD14+ECs in the systemic inflammation and cardiovascular comorbidities associated with psoriasis. Additionally, phosphorylated NF-κB was found in psoriatic CARD14+ CD31+ ECs, demonstrating this pathway is active in dermal ECs in psoriasis. Transfection of dermal ECs with psoriasis-associated CARD14 mutations resulted in increased expression of several chemokines, including CXCL10, IL-8, and CCL2. These results provide preliminary evidence that CARD14 expression in ECs may contribute to psoriasis through increased expression of chemokines and facilitating recruitment of immune cells into skin.

CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for Psoriasis

“…Harden et al (2014) also showed that CARD14 expressed in dermal endothelial cells could modulate the expression of chemokines such as CXCL8, CXCL10, and CCL2, which sensitize the skin vasculature of psoriasis patients bearing CARD14 mutations to inflammation. Because psoriasis is often associated with cardiovascular comorbidities, these observations might also imply a role for CARD14 in cardiovascular disease (Yim and Armstrong, 2016).…”

Activating CARD14 Mutations Are Associated with Generalized Pustular Psoriasis but Rarely Account for Familial Recurrence in Psoriasis Vulgaris

“…Conversely, CARD14 mRNA is virtually undetectable in T-lymphocytes and monocytes, suggesting that the gene is specifically required for the maintenance of skin immune homeostasis (Fuchs-Telem et al, 2012;Harden et al, 2014). In keeping with this notion, gain-of-function CARD14 mutations have been linked to a number of inflammatory dermatoses.…”

“…The gene is most prominently expressed in skin, as transcript levels are high in keratinocytes and moderately abundant in dermal endothelial cells (Fuchs-Telem et al, 2012;Harden et al, 2014).…”

A psoriasis és az oxidatív stressz

“…A CARD-14 protein többek között felelős az NFκB aktivitásának regulációjáért, így közvetett markere lehet az NFκB aktivitásának. A psoriasisos beteg endothelsejtjein kimutatott CARD-14-pozitivitás összefüggésben lehet a szisztémás gyulladás kialakulásával, továbbá a cardiovascularis komorbiditások megjelenésével [8].…”