Keratin 17: A Critical Player in the Pathogenesis of Psoriasis

Abstract

Keratin 17 (K17) is an intermediate filament protein present in the basal cells of complex epithelia, such as nails, hair follicles, sebaceous glands, and eccrine sweat glands. Studies have shown that it is expressed aberrantly in the suprabasal keratinocytes of psoriatic lesions, compared to in normal epidermis. K17 is also closely associated with the immune system and plays an important role in the pathogenesis of psoriasis. In this review, we present our experimental findings concerning the role of K17 in psoriasis, and compare them to results published in the literature. Our results show that cytokines related to Th17 and IL-22-producing (where Th17 is T helper cells, type 17 and IL is interleukin) CD4(+) T cells, including IL-17A and IL-22, upregulate the expression of K17 in keratinocytes. In addition, K17 stimulates autoreactive T cells and promotes the production of psoriasis-associated cytokines. Our findings lend support to the hypothesis that a K17/T-cell/cytokine autoimmune loop is involved in the pathogenesis of psoriasis. We therefore review the current understanding of the K17 immunoregulation, including its expression and direct/indirect effects on immune responses. Pertinent strategies for the treatment of psoriasis are also discussed.

The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis

“…Keratinocyte-derived proteins [18][19][20][21][22]42 , among which keratins, were previously identified as autoantigens, especially in a subset of patients with psoriasis linked to group-A b-hemolytic streptococcal throat infections. Our study now identifies the AMP LL37 as a new autoantigen in psoriasis that is recognized by circulating T cells in 46% of psoriasis patients and up to 75% of patients with moderate-to-severe psoriasis.…”

“…We also tested reactivity to keratins, as these proteins were identified as autoantigens in a subset of psoriasis patients [18][19][20][21][22] . In keeping with the literature [18][19][20][21][22] , we detected reactivity to Keratins that was statistically significant for Keratin17 ( Supplementary Fig. 3, lefts panels).…”

Regulation of C-X-C chemokine gene expression by keratin 17 and hnRNP K in skin tumor keratinocytes

“…The sharp sensitivity of Krt17 expression to pro-inflammatory and pro-tumorigenic signals, such as IFN (Vogel et al, 1995), is well-established (DePianto et al, 2010;Jin and Wang, 2014). The K17/hnRNP K/CXCR3 signaling axis exposed by our study implicates K17 in positive feedback loops that not only promote but also sustain a specific type of inflammation and immune response in chronic skin disease settings.…”

“…Expression of CXCR3 and its ligands is markedly elevated in psoriatic skin (Chen et al, 2010), in which K17 contributes to disease pathogenesis (Jin and Wang, 2014). CXCR3 and its ligand CXCL11 are both required for wound repair in healthy skin (Yates et al, 2011), a physiological setting in which K17 expression is robustly induced (McGowan and Coulombe, 1998).…”

“…In skin psoriasis, which is in part driven by inflammation and various types of immune effectors, expression of CXCR3 and its ligands are significantly elevated (Chen et al, 2010). K17 has also been shown to contribute to the pathogenesis of psoriasis (Jin and Wang, 2014). Accordingly, the emerging connection between K17 and the expression of CXCR3 ligands and other pro-inflammatory cytokines (Lo et al, 2010) may also represent a defining step in hyperproliferative and inflammatory disorders related to tumorigenesis.…”