Toll-like Receptors: Pivotal Players in Inflammation
Immune cells sense danger signals coming from either pathogens or damaged/abnormal host cells through a variety of receptors. A pivotal group of these receptors is the Toll-Like Receptor (TLR) family, which is comprised of at least 10 members. TLRs 1, 2, 4, 5, 6, and 10 recognize pathogens on the basis of components of their structure, while TLRs 3, 7, 8, and 9 react to elements of the pathogen's nucleic (DNA or RNA) acids. TLRs that respond to nucleic acids appear to have a special role in detecting and protecting against viral infection. These TLRs are found in dendritic cells, specialized immune cells that present foreign antigens to other immune cells that in turn use this information to recognize and destroy the invaders. TLR8 is found in the classical human myeloid dendritic cells that stimulate T cell responses. In contrast, TLR7 and TLR9 are found in human plasmacytoid dendritic cells, a subset of dendritic cells specialized in the production of type I interferons (IFN-α/β), potent proteins with antiviral and immunomodulatory effects. In addition to stimulating the production of IFNs, activation of TLRs results in the production of other important inflammation-inducing factors, including tumor necrosis factor (TNF) and interleukin (IL)-1β.
Under certain circumstances, TLR 3, 7, 8, and 9 can also respond to the body's own nucleic acids. Dying host cells are a rich source of self-RNA and DNA. RNA or DNA that is aberrantly transported to sites within dendritic cells containing TLR7 and TLR9 activate these receptors, triggering a cascade of immune responses and cellular interactions. Chronic activation of these responses in turn causes tissue inflammation and destruction and the release of more self-DNA and RNA from the dying cells, resulting in a cycle of self-perpetuating damaging responses. The activation of TLR7 and TLR9 by the body's own nucleic acids has been shown to be a key step in the development of SLE and is suspected to be involved in the genesis of many other auto-inflammatory diseases. The possible involvement of TLR 7, 8, and 9 and dysregulated dendritic cells is supported by an increased expression of type 1 IFN-related genes that can be detected in the blood of patients with SLE, cutaneous lupus, rheumatoid arthritis, psoriasis, and Sjogren's syndrome, suggesting that dysregulated dendritic cell activation may be a more general feature of autoimmune disease.