Endosomal Toll-like Receptors: Rheostats of Inflammation and Diseases

Toll-like receptors (TLRs) are major components of the innate immune system playing an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs).Till date, thirteen mammalian TLR members (TLR1-13) have been identified, ten in human and thirteen in mice. The human TLRs are further divided into two subgroups: six surface bound (TLR 1, 2, 4, 5, 6 and 10) and four within the intracellular endosomal compartment (TLR 3, 7, 8, and 9) of TLR-expressing cells. Extracellular TLRs identify structural components of pathogens like lipopolysaccharides, peptidoglycan, βglucan etc. Whereas endosomal TLRs are specific to pathogenic nucleic acids viz. double-stranded RNA (dsRNA), single-stranded RNA (ssRNA) CpG ODN etc. These sensors are expressed in a number of cell types including conventional dendritic cells (cDCs), plasmacytoid DCs (pDCs), macrophages, and B cells. Interaction with specific pathogenic antigens incites TLRs to trigger the transcription followed by synthesis of pro-inflammatory cytokines. Both the groups of TLRs have been particularly implicated in the pathogenesis of cancer, allergy and autoimmune disorders. However the present chapter is focused on endosomal TLRs and their crucial role in inflammation and related diseases. The initial part is focused on structural features of TLRs, specific ligands and thereafter intracellular signaling arbitrating the release of inflammatory mediators. In addition the role of endosomal TLRs in disease aggravation is also discussed. Moreover, the inhibition of activation or ability of modulation of these endosomal TLRs with specific ligands has also been illustrated as complementary therapeutic agents to combat various human ailments.

Keywords: Cytokine, Disorders, Ectodomain, Endosome, Glycoproteins, Immune system, Immunomodulation, Inflammation, Leucine rich repeats, Microorganisms, Nucleic acid, Pattern recognition receptors, Therapeutics, Toll-like receptors, Transmenbrane.