Keratin 6, 16 and 17-Critical Barrier Alarmin Molecules in Skin Wounds and Psoriasis.

cells Review Keratin 6, 16 and 17—Critical Barrier Alarmin Molecules in Skin Wounds and Psoriasis Xiaowei Zhang 1,† , Meimei Yin 1,† and Ling-juan Zhang 1,2, * 1 2 * † School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA Correspondence: These authors contribute equally to this work. Received: 10 July 2019; Accepted: 28 July 2019; Published: 1 August 2019



 Abstract: Located at the skin surface, keratinocytes (KCs) are constantly exposed to external stimuli and are the first responders to invading pathogens and injury. Upon skin injury, activated KCs secrete an array of alarmin molecules, providing a rapid and specific innate immune response against danger signals. However, dysregulation of the innate immune response of KCs may lead to uncontrolled inflammation and psoriasis pathogenesis. Keratins (KRT) are the major structural intermediate filament proteins in KCs and are expressed in a highly specific pattern at different differentiation stages of KCs. While KRT14-KRT5 is restricted to basal proliferative KCs, and KRT10-KRT1 is restricted to suprabasal differentiated KCs in normal skin epidermis, the wound proximal KCs downregulate KRT10-K1 and upregulate KRT16/KRT17-KRT6 upon skin injury. Recent studies have recognized KRT6/16/17 as key early barrier alarmins and upregulation of these keratins alters proliferation, cell adhesion, migration and inflammatory features of KCs, contributing to hyperproliferation and innate immune activation of KCs in response to an epidermal barrier breach, followed by the autoimmune activation of T cells that drives psoriasis. Here, we have reviewed how keratins are dysregulated during skin injury, their roles in wound repairs and in initiating the innate immune system and the subsequent autoimmune amplification that arises in psoriasis. Keywords: keratins; epidermal keratinocytes; barrier alarmins; skin wounds; psoriasis; proliferation; innate immune responses; autoimmune 1. Introduction: As the first physical and immunological barrier of the human body, the skin is a highly specialized organ composed of three primary layers: the outermost epidermis, the dermis and dermal white adipose tissue [1–4]. The epidermis, derived from a single layer of progenitor cells in embryos to a multilayered stratified epithelium during development, is at the front line of defense and is constantly exposed to a variety of environmental insults such as mechanical trauma, pathogens and chemical irritations [5–7]. As a result, keratinocytes, the most abundant cell type of the skin epidermis, has evolved to provide rapid and situation-specific innate immune responses upon sensing danger signals. During skin injury or infection, damage-associated molecular patterns (DAMPs) released by host necrotic cells or pathogen-associated molecular patterns (PAMPs) are recognized by keratinocytes through pattern recognition receptors (PRRs), leading to the rapid induction of “alarmins”, such as antimicrobial peptides, the S100 family of proteins and proinflammatory cytokines/chemokines that initiate a host innate immune defense against insults. These keratinocyte-derived alarmins not only directly attack invading pathogens, but can also attract or activate immune cells (such as dendritic cells, macrophages, neutrophils and T cells) and promote the development of adaptive immunity against pathogens or danger signals for long term protection. Cells 2019, 8, 807; doi:10.3390/cells8080807 www.mdpi.com/journal/cells Cells 2019, 8, 807 2 of 14 Keratins (KRT), the major components of the epithelial cytoskeleton, are responsible for maintaining the structural stability and integrity of keratinocytes. So far, more than 54 mammalian keratins have been identified, contributing to ~30–80% of total protein and forming the ~10 nm intermediate filaments (IFs) in keratinocytes [7–9]. These highly diverse keratins are subdivided into two classes based on their pH: The acidic type I keratins (KRT9-KRT40) and the neutral–basic type II keratins (KRT1-KRT8) [10–12]. Keratins form a heterodimer between one type I keratin and one type II keratin, while self-assembling into antiparallel, staggered tetramers, forming an intermediate filament through longitudinal and lateral interaction [9]. Genes encoding type I and II keratins are clustered into two distinct chromosomal regions including chromosome17q12–q21 for type I keratins (except K18) and chromosome12q11–q13 for all type II keratins and KRT18 [13–15]. Despite their distinct locations on the genome, specific pairs of type I and type II keratins exhibit a highly specific and consistent expression pattern within a specific epidermal cell layer [11,16]. For example, in the interfollicular epidermis, KRT14-KRT5 is the major type I-type II keratin pair expressed in proliferative basal keratinocytes, whereas differentiated keratinocytes in the suprabasal layers downregulate KRT14-KRT5 and express KRT10-KRT1 as the major keratin pair. During wounding, stressed keratinocytes rapidly induce de novo transcription of KRT16/17-KRT6, whose expression is normally restricted to epidermal cells of glabrous skin, the oral mucosa, and several appendages [7]. Epidermal keratinocytes are constantly exposed to physical stress, and therefore a primary role of the keratin intermediate filament is to act as a flexible scaffold and provides resilience, enabling epidermal cells to resist mechanical stress [17]. Similar to other IFs, keratins have a head-rod-tail structure, with a central α-helical rod domain that is essential for intermediate filament formation [18,19]. Keratin IFs extend from the desmosomes to the nuclear membrane, providing tissue resilience to resist environmental stresses [20]. In addition to providing structural support to epithelial cells, growing evidence has shown that keratins also regulate cell proliferation, migration, adhesion and inflammatory features of keratinocytes [7,16,21]. Mutation or abnormal expression of keratin proteins is associated with a variety of skin diseases, such as skin blistering diseases (Epidermolysis bullosa simplex and Epidermolytic hyperkeratosis), psoriasis and skin tumors (squamous cell carcinoma and basal cell carcinoma). In this review, we have focused on the role of keratin proteins during skin wounding and how dysregulation of these keratins may lead to keratinocyte hyperproliferation and the development of an autoimmune amplification loop that drives the pathogenesis of psoriasis. 2. Keratin Expression During Skin Development and in Skin Diseases Keratins have been widely used as marker proteins for various epithelial cell proliferation or differentiation stages as well as for epidermal disease diagnostics. In normal interfollicular skin, the expression of KRT14-KRT5 is considered to be the hallmark of basal keratinocytes including a cluster of progenitor cells, where (...truncated)