Toll-Like Receptors in Skin
Section snippets
Editorial Comment
Dr. Miller and his colleagues at the University of California - Los Angeles have been national leaders in elucidating the roles of a family of proteins called Toll-like receptors (TLRs) in processes as diverse as Staphylococcus aureus skin infections, acne vulgaris, and leprosy infection. TLRs are a highly conserved family of pattern recognition receptors that have emerged as critical sensors of bacterial, fungal, and viral pathogens by recognizing conserved components of these microorganisms,
Innate and adaptive immunity
Innate immunity was once considered to be an early nonspecific proinflammatory response whose primary function was to recruit and activate phagocytes such as neutrophils and monocytes/macrophages to phagocytize microorganisms [9], [10]. It is now known that the innate immune response has considerable specificity that is directed against conserved molecular patterns of components of microorganisms, which are called pathogen-associated molecular patterns (PAMPs) [9], [10]. The receptors on immune
Toll-like receptors
TLRs are transmembrane glycoproteins that contain an ectodomain of leucine-rich motifs, which is involved in recognition of components of microbes [6], [7], [8]. TLRs also contain a transmembrane domain and a cytoplasmic tail domain that is homologous to the interleukin-1 receptor and is responsible for initiating various intracellular signaling cascades (Fig. 1) [6], [7], [8]. These signaling cascades include activation of nuclear factor-κB (NF-κB), which is a key transcription factor that
Toll-like receptor signaling and immune responses
Activation of TLRs by their ligands results in initiation of several signaling cascades, which eventually result in expression of cytokines (eg, tumor necrosis factor [TNF]α, interleukin [IL]-1β, IL-6, IL-12), chemokines (IL-8, growth-regulated oncogene [GRO]-α, monocyte chemoattractant protein [MCP]-1, -2, -3, -4, macrophage inflammatory protein [MIP]1α/β, and Regulated upon Activation, Normal T-cell Expressed, and Secreted [RANTES]), antimicrobial peptides, (beta-defensins and cathelicidin),
Toll-like receptors can induce a vitamin D–dependent antimicrobial pathway
Recently, Liu and colleagues [15], [16] demonstrated that activation of TLR2/1 on human monocytes/macrophages up-regulated a vitamin D-1-hydroxylase (CYP27B1) and the vitamin D receptor (VDR) (Fig. 4). This activity of TLR2/1 resulted in the conversion of the inactive form of vitamin D (25D3) to its active form (1,25D3), which subsequently activated the VDR and led to the production of the antimicrobial peptide cathelicidin [15], [16]. Since cathelicidin has microbicidal activity against a
Toll-like receptor expression and function of skin-specific cells
There are many different cell types in human skin that express TLRs [1], [2], [3]. In the epidermis, keratinocytes have been shown to express functional TLRs. In addition, there are resident and trafficking immune system cells in the skin that express TLRs, including Langerhans cells (LCs), monocytes/macrophages, dendritic cells (DCs), T and B lymphocytes, and mast cells [1], [2], [3]. Last, endothelial cells of the microvasculature and stromal cells such as fibroblasts and adipocytes also
Atopic dermatitis
Atopic dermatitis or eczema is an inflammatory skin disease that is associated with a hereditary predisposition to atopic conditions, which include allergic rhinitis, allergic keratoconjuntivitis, asthma, and eczema [5]. Clinically, atopic dermatitis is characterized by the presence of inflammatory skin lesions that are extremely pruritic [5]. Like other allergic diseases, the pathophysiology of atopic dermatitis involves a Th-2 type immune response in the skin. The role of TLRs in the
Staphylococcus aureus
S aureus is a gram-positive bacterium that is the most common cause of bacterial skin infections in humans such as impetigo, folliculitis/furunculosis, and cellulitis. TLR2 has been shown to recognize various components of S aureus, including peptidoglycan and lipopeptides [62], [63], [64]. In addition, the TLR2/6 heterodimer along with CD36 has been shown to recognize S aureus lipoteichoic acid [65]. A recent study demonstrated that TLR2 on primary human keratinocytes contributed to
Summary
TLRs have emerged as a major class of PRRs that are involved in detecting invading pathogens in the skin and initiating cutaneous immune responses. TLRs are expressed on many different cell types in the skin, including keratinocytes and Langerhans cells in the epidermis. Each TLR can recognize a different microbial component and there are differences among the TLR signaling pathways, which lead to distinct immune responses against a given pathogen. Certain TLRs have been implicated in the
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