Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin

Abstract

The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.

The Immune Functions of Keratinocytes in Skin Wound Healing

“…Keratinocytes express various PRRs, including Toll-like receptors (TLRs), C-type lectin receptors, nucleotide-binding oligomerization domain-like receptors, and retinoic-acid-inducible gene I (RIG-I)-like receptors [ 9 ]. Ligand recognition via specific PRRs leads to the subsequent activation of distinct signaling pathways and the production of inflammatory cytokines, chemokines, and host antimicrobial molecules [ 10 ]. After being released from keratinocytes, these factors serve an important function in activating skin-resident immune cells and recruiting circulating immune cells to the wound site [ 8 ].…”

“…In addition to TLRs, RIG-I-like receptors (RLRs) are important cytosolic nucleic acid sensors in keratinocytes. When bound to dsRNA or dsDNA, they trigger an antiviral defense by activating type I IFN production [ 10 , 29 ]. Type I IFNs are critical regulators of host antiviral defense, as they can promote myeloid dendritic cell maturation, T-cell proliferation, and priming of CD8+ T-cells, and they stimulate B-cell differentiation into antibody-secreting plasma cells [ 30 ].…”

“…On the other hand, keratinocytes also sense wound microenvironmental cues, including the signals from immune cells and respond with changed cellular functions [ 38 ]. The key cytokines, chemokines, and their receptors involved in keratinocyte immune function have been reviewed recently [ 10 ]. Here, we will focus on the related evidence implicated in the wound healing process.…”

“…Neutrophils produce cytokines (e.g., TNF-α, IL-1β, and IL-6) and chemokines (e.g., CXCL2, CXCL8, and monocyte chemoattractant protein 1, MCP-1, also referred to as CCL2) to attract more immune cells, thus amplifying the inflammatory response [ 48 ]. In part, neutrophil-secreted TNF-α, IL-1β, and IL-6 also promote keratinocyte immune responses and proliferation [ 10 , 42 , 43 , 49 ]. After completing their mission, apoptotic neutrophils express phosphatidylserine (PS), Annexin I, and calreticulin on their cell surface, which serve as signals to initiate neutrophil engulfment by macrophages, diminishing the inflammatory phase [ 50 ].…”

Going, Toll-like receptors in skin inflammation and inflammatory diseases

“…The immunological roles of keratinocytes and γδT cells in skin immunity, including their role in orchestrating T cell immunity in the skin have been described somewhere else (Jiang et al, 2020[ 81 ]; Klicznik et al, 2018[ 96 ]; Macleod and Havran, 2011[ 124 ]). The prenatal skin expresses the same spectrum of TLRs as adult human skin (Iram et al, 2012[ 75 ]).…”