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.
Highlights
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 [1,2,3,4]
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
The fact that KRT6, 16, and 17 transcript levels are rapidly induced in wound-proximal keratinocytes within hours after injury in vivo or in the ex vivo model using human skin explants in the absence of T cells [48], suggesting that the initial induction of these keratins during wounding are likely to be triggered by innate immune activation of keratinocytes in response to damage-associated molecular patterns (DAMPs) or cytokines, such as dsRNA and IL1β, released locally by skin resident cells
Summary
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 [1,2,3,4]. 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 directly attack invading pathogens, but can 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. 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
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