Abstract
As the key defense molecules originally identified in Drosophila, Toll-like receptor (TLR) superfamily members play a fundamental role in detecting invading pathogens or damage and initiating the innate immune system of mammalian cells. The skin, the largest organ of the human body, protects the human body by providing a critical physical and immunological active multilayered barrier against invading pathogens and environmental factors. At the first line of defense, the skin is constantly exposed to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and TLRs, expressed in a cell type-specific manner by various skin cells, serve as key molecules to recognize PAMPs and DAMPs and to initiate downstream innate immune host responses. While TLR-initiated inflammatory responses are necessary for pathogen clearance and tissue repair, aberrant activation of TLRs will exaggerate T cell-mediated autoimmune activation, leading to unwanted inflammation, and the development of several skin diseases, including psoriasis, atopic dermatitis, systemic lupus erythematosus, diabetic foot ulcers, fibrotic skin diseases, and skin cancers. Together, TLRs are at the interface between innate immunity and adaptive immunity. In this review, we will describe current understanding of the role of TLRs in skin defense and in the pathogenesis of psoriasis and atopic dermatitis, and we will also discuss the development and therapeutic effect of TLR-targeted therapies.
Highlights
The skin, poised at the interface between the host body and the environment, is constantly exposed to pathogens and environmental insults and has evolved to provide rapid and specific immune responses to these stimuli
During skin injury, damaged cells release damage-associated molecular patterns (DAMPs) such as double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and DNA, and we have found that the antimicrobial peptide LL37 which is upregulated during wounding enables dsRNA recognition in keratinocytes through the TLR3 and mitochondrial MAVS signaling pathway, leading to IFNβ production from KC or plasmacytoid dendritic cells (pDCs), respectively [22, 61]
The effect of IMQ is mediated by recruitment and activation of pDC, conventional DCs (cDCs), or macrophages through TLR7/TLR8, leading to the production of cytokines including type 1 IFNs, IL1, interleukin 6 (IL6), and TNF followed by the development of cell-mediated adaptive immunity against cancer cells [109]
Summary
The skin, poised at the interface between the host body and the environment, is constantly exposed to pathogens and environmental insults and has evolved to provide rapid and specific immune responses to these stimuli. Precise and situation-specific innate immune responses of skin cells to insults lead to rapid induction of host defense molecules including antimicrobial peptides (AMPs) and proinflammatory cytokines that shapes the adaptive immune responses, leading to immediate as well as long-term protection against pathogens or physical dangers. Mammalian TLRs were first identified based on their sequence homology with the Drosophila Toll gene, which was originally discovered by Dr Jules Hoffmann as the crucial receptor detecting microorganisms and activating the fly’s innate immune defense. While PRR activation is essential for inflammatory responses that initiate skin’s host defense against invasive pathogens, overactivation of PRRs often leads to uncontrolled inflammation and the subsequent development of autoimmunity and/or inflammatory skin diseases, such as psoriasis, atopic dermatitis, systemic lupus erythematosus, and diabetes-induced impaired wound healing [11,12,13]. We will review current literatures on the role of TLRs in host defense and how aberrant activation of TLRs leads to the development of psoriasis and atopic dermatitis and recent advances in therapeutic targeting of TLR to treat these skin diseases
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