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

Abstract

The Indian Ayurvedic physicians knew the concept of inflammation dating back to 1500 BC. The continuous progress in the immunology of inflammation has explained its undiscovered mechanisms. For example, the discovery of Toll-like receptor 4 (TLR4) in humans (1997) has revolutionized the field of infection biology and innate immunity. The laboratory mice have shown twelve TLRs and express TLR10 (CD290) as a disrupted pseudogene, and humans have ten functional TLRs. Now, it is well established that TLRs play a significant role in different infectious and inflammatory diseases. Skin inflammation and other associated inflammatory diseases, including atopic dermatitis (AD), acne vulgaris, and psoriasis, along with many skin cancers are major health problems all over the world. The continuous development in the immunopathogenesis of inflammatory skin diseases has opened the window of opportunity for TLRs in studying their role. Hence, the manuscript explores the role of different TLRs in the pathogenesis of skin inflammation and associated inflammatory diseases. The article starts with the concept of inflammation, its origin, and the impact of TLRs discovery on infection and inflammation biology. The subsequent section describes the burden of skin-associated inflammatory diseases worldwide and the effect of the geographical habitat of people affecting it. The third section explains skin as an immune organ and explains the expression of different TLRs on different skin cells, including keratinocytes, Langerhans cells (LCs), skin fibroblasts, and melanocytes. The fourth section describes the impact of TLRs on these cells in different skin-inflammatory conditions, including acne vulgaris, AD, psoriasis, and skin cancers. The article also discusses the use of different TLR-based therapeutic approaches as specific to these inflammatory skin diseases.

Keywords: TLRs; atopic dermatitis; inflammation; melanoma; psoriasis; skin.

Table 1. TLRs expressed in human skin cells, their location, PAMPs, and DAMPs

Figure 1. Schematic representation of human skin. A: Anatomical section of human skin showing epidermis, dermis, and adipose layer along with different immune cells and skin cells. B: Different layers of epidermis, stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. LCs, melanocytes, keratinocytes and other immune cells (macrophages, T cells, NKT cells, and B cells etc.) present in the dermis and epidermis are also shown.

Figure 2. Schematic representation of TLR4, TLR7/TLR8, and TLR9-dependent signaling pathways. TLR 4 activation induces NF-κB activation through both MyD88-dependent and MyD88-independent but TRIF-dependent signaling pathways. Whereas, TLR7/TLR8 activation upon binding to their corresponding ligands induces MyD88-dependent signaling pathways to induce IRF7-dependent IFN synthesis, which have potent immunomodulatory action on both innate and adaptive immune cells. The TLR9 activation upon recognizing and binding to its ligand involves TRIF-dependent signaling pathway for IFN synthesis. The details are mentioned in the text.