The Role of Toll-like Receptors in the Pathogenesis and Treatment of Dermatological Disease

toll like receptors role in dermatological disease
  • Jamie E. McInturff *. 1 ,
  • Robert L. Modlin *. † ,
  • Jenny Kim *. .
  • * Division of Dermatology, CHS David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  • † Department of Microbiology and Immunology, CHS David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Received 25 February 2004, Revised 30 June 2004, Accepted 2 July 2004, Available online 8 December 2015

Toll-like receptors (TLR) are crucial players in the innate immune response to microbial invaders. These receptors are expressed on immune cells, such as monocytes, macrophages, dendritic cells, and granulocytes. Importantly, TLR are not only expressed by peripheral blood cells, but their expression has been demonstrated in airway epithelium and skin, important sites of host–pathogen interaction. Host cells expressing TLR are capable of recognizing conserved pathogen-associated molecular patterns, such as lipopolysaccharide and CpG DNA, and their activation triggers signaling pathways that result in the expression of immune response genes and cytokine production. As TLR are instrumental in both launching innate immune responses and influencing adaptive immunity, regulation of TLR expression at sites of disease such as in leprosy, acne, and psoriasis may be important in the pathophysiology of these diseases. Furthermore, since TLR are vital players in infectious and inflammatory diseases, they have been identified as potential therapeutic targets. Indeed, synthetic TLR agonists such as imiquimod have already established utility in treating viral pathogens and skin cancers. In the future, it seems possible there may also be drugs capable of blocking TLR activation and thus TLR-dependent inflammatory responses, providing new treatment options for inflammatory diseases.

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In response to pathogen exposure, a host employs both the innate and adaptive arms of the immune system to protect against infection. The innate immune response utilizes both physical barriers such as skin and mucosal epithelium as a means of avoiding infection and rapid cellular responses enacted by dendritic cells (DC), monocytes, natural killer cells, granulocytes, and epithelial cells to

protect a newly infected host. These cells express pattern recognition receptors that mediate responses to pathogen-associated molecular patterns (PAMP) that are conserved among microorganisms. Human Toll-like receptors (TLR) are one such family of pattern recognition receptors capable of initiating innate immune responses and influencing subsequent adaptive immune responses ( Medzhitov et al. 1997 ). Currently, 10 TLR are known to be expressed in humans, and the microbial ligands for many of these receptors have been identified ( Figure 1 ). The ligands include molecules uniquely found in microbes such as bacterial cell wall components. More specifically, TLR4 mediates host responses to bacterial lipopolysaccharide (LPS) from Gram-negative bacteria such as Escherichia coli. whereas TLR2 mediates responses to peptidoglycan from Gram-positive bacteria such as Staphylococcus aureus ( Poltorak et al. 1998 ; Yoshimura et al. 1999 ). In addition, TLR2/1 heterodimers mediate responses to tri-acylated lipoproteins, and TLR2/6 heterodimers mediate responses to di-acylated lipoproteins ( Brightbill et al. 1999 ; Ozinsky et al. 2000 ). Not all TLR, however, mediate innate responses to components of bacterial cell walls. For instance, TLR9 mediates the response to unmethylated CpG DNA found in bacterial genomes, whereas TLR3 mediates the response to viral double-stranded RNA ( Hemmi et al. 2000 ; Alexopoulou et al. 2001 ). Furthermore, TLR5 is involved in mediating the host response to bacterial flagellin, and recently single-stranded RNA was identified as the ligand for TLR8 in humans and TLR7 in mice ( Hayashi et al. 2001 ; Diebold et al. 2004 ; Heil et al. 2004 ).

Human Toll-like receptors display specificity in their recognition of pathogen-associated molecular patterns and/or synthetic compounds.

TLR are transmembrane proteins with the extracellular portion composed of leucine-rich repeats, whereas the intracellular portion shares homology with the cytoplasmic domain of the IL-1 receptor. When TLR are activated by ligand exposure, the intracellular domain of the TLR may trigger a MyD88-dependent pathway that ultimately leads to the nuclear translocation of the transcription factor NF

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Category: Disease

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