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

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: autoimmune; barrier alarmins; epidermal keratinocytes; innate immune responses; keratins; proliferation; psoriasis; skin wounds.

Figure 1

Keratin expression and function in normal skin epidermis or in wounded/psoriatic skin epidermis. In normal skin epidermis, basal keratinocytes express type I and type II keratin pair KRT14 (K14)-KRT5 (K5), which is necessary for maintaining keratinocyte proliferation by increasing AKT phosphorylation, promoting cell cycle progression and inhibiting spontaneous differentiation of keratinocytes. In contrast, cells located at the suprabasal epidermal layers express K10-K1 as the dominant keratin pair, and this keratin pair promotes terminal differentiation of keratinocytes by decreasing ERK1/2 phosphorylation, inhibiting cell cycle progression, and increasing Notch1 expression while maintaining nuclear integrity of differentiating cells. During skin injury or in psoriasis, suprabasal keratinocytes downregulate K10-K1, upregulate K14-K5 and strongly induce the expression of K16/K17-K6. The K16-K6 keratin pair functions to maintain collective cell migration and integrity by increasing cell-cell and cell-matrix contact, decreasing cell migration and directionality while maintaining mechanical integrity. K17 can pair with either K6 or K5 to drive keratinocyte hyperproliferation by increasing cell size and increasing protein synthesis. K17 can also induce Th1/Th17 cytokine production from keratinocytes, and K17 peptides can also serve as an autoantigen to promote antigen presenting cell (APC)-T cell activation, leading to autoimmune amplification during psoriasis pathogenesis.

Figure 2

Model for the regulation of Keratin 6, 16 and 17 during skin wounding and in psoriasis. During skin injury, damaged keratinocytes (KCs) release a variety of damage-associated molecular patterns (DAMPs), such as nucleic acids (RNA or DNA) and proteins (such as IL1β). Recognition of these DAMPs by their cognate receptors, such as IL1β by IL1R, EGF by EGFR, dsRNA by TLR3 and/or VEGF by VEGFR, lead to the activation of downstream signaling molecules, including MAPKs (ERK1/2 and p38) and transcription factors CEBPβ, NFκB, NRF2 and AP1, which then translocate to the nucleus and mediate the transcription of K6, 16 and 17. K6 protein can interact with myosin IIA, promoting cell adhesion and resilience that is necessary for KCs to resist mechanical stress during wounding. Furthermore, the K17 protein can promote protein synthesis and cell proliferation by activating the mTOR-AKT pathway. K17 can also translocate to the nucleus, regulating the expression of proinflammatory cytokines through chromatin binding and transcription. In addition, peptides derived from K17 can function as autoantigens to activate conventional DCs (cDC), which then secrete cytokines (TNF, IL12 and IL23) that promote Th1, Th17 and/or Th22 T cell activation. T cell-derived cytokines, including IFNγ, IL17A and IL22, can in turn act on their respective cell receptors that are expressed on keratinocytes, leading to activation of the ERK1/2 and STAT1/3, which further increases the expression of keratin genes, forming an autoimmune positive feedback loop that ultimately drives psoriasis pathogenesis.