Toll-like receptors (TLRs) are single transmembrane cell-surface receptors, which have a key role in the innate immune system. TLRs generally exist as homodimers (heterodimers have been reported) and are found on immune cells; macrophages, B lymphocytes and mast cells.
The family of Toll-like receptors (TLRs), which are localized either to the cell surface or within endosomes, is the major and most extensively studied class of Pathogen recognition receptors (PRRs). The Toll gene was identified as a gene essential for the dorsal-ventral development during embryogenesis as well as in the antifungal response in Drosophila melanogaster. Structurally, TLRs are integral glycoproteins characterized by an extracellular or luminal ligand-binding domain containing leucine-rich repeat (LRR) motifs and a cytoplasmic signaling Toll/interleukin-1 (IL-1) receptor homology (TIR) domain. Ligand binding to TLRs through PAMP-TLR interaction induces receptor oligomerization, which subsequently triggers intracellular signal transduction. The TLR family now consists of thirteen mammalian members. To date, ten TLRs have been identified in humans (hTLRs) while in the mouse twelve TLRs (mTLRs) have been recognized. The genes corresponding to all ten TLRs genes identified in humans have been fully cloned in pigs. Individual TLRs are differentially distributed within the cell. TLR1, TLR2, TLR4 and TLR6 are expressed on the cell surface, as demonstrated by positive staining of the cell surface by specific antibodies. In contrast, TLR3, TLR7, TLR8 and TLR9 have been shown to be expressed in intracellular compartments such as endosomes. Each TLR recognize distinct Pathogen-associated molecular patterns (PAMPs) derived from various microbial pathogens, including viruses, bacteria, fungi, and protozoa. In addition to the recognition of PAMPs, TLRs may also be able to recognize endogenous signals such as heat shock proteins and products of necrotic cells and thus may be involved in auto-immune phenomena or activation of tissue repair.
TLRs are preferentially –but not exclusively- expressed in Antigen-presenting cells (APCs), including macrophages and B lymphocytes. TLR signaling causes DCs to become APCs by the induction of costimulatory molecules (such as CD80 and CD86), the up-regulation of major histocompatibility complex (MHC) molecules and the secretion of cytokines and chemokines. In fact, TLRs have been identified in most cell types, expressed either constitutively or in an inducible manner in the course of infection. As aforementioned, TLRs play a central role in the recognition of a wide array of microbial components. Actually, most Gram-positive and -negative bacteria can activate additional TLRs via alternative PAMPs present in the cell membrane, cell wall, or intracellularly. As general rule, it is considered that the lipid A portion of LPS from Gram-negative bacteria is recognized through the TLR4/MD2/CD14 complex. When LPS is present in the blood stream, it is immediately captured by LBP, which converts oligomeric micelles of LPS to a monomer for delivery to CD14. Then, CD14 concentrates LPS for binding to the TLR4/MD2 complex.
TLR2 is a versatile receptor, as it recognizes a variety of microbial components, including lipoproteins/lipopeptides from Gram positive/negative bacteria and PG, LTA from Gram-positive bacteria. These two last components can trigger a toxic shock syndrome similar to that induced by LPS. MD2 enhances TLR2-mediated recognition, as it is physically associated with this receptor, but this association is weaker than with TLR4. Two characteristics have been proposed as mechanisms that could explain why TLR2 recognizes a wide spectrum of microbial components. The first explanation is that TLR2 forms heterophilic dimers with other TLRs such as TLR1 and TLR6, to discriminate subtle differences between triacyl and diacyl lipopeptides, respectively. The second explanation involves the ability of TLR2 to recognize fungal-derived components. Indeed, TLR2 collaborates with distinct types of receptors such as dectin-1, that is a lectin family receptor for the fungal cell wall component β-glucan.
In the case of Gram-positive cocci responsible for meningitis, it is now known that TLR2 is involved in the recognition of S. pneumoniae and in the expression of the pro-inflammatory response. In this case, TLR2 is the receptor for pneumococcal cell wall, including PG. However, pneumolysin, a crucial virulence factor of S. pneumoniae virulence, triggers the inflammatory response via TLR4, denoting that the host can synergistically activate different TLRs for S. pneumoniae recognition. As for GBS, researchers have found that this pathogen elicits cell recognition through TLR2 and a MyD88-dependent pathway, events that lead to cytokine and nitric oxide (NO) production, molecules that have a direct negative impact on neurons, as there is induction of apoptosis in these cells via a caspase-8 pathway. Moreover, GBS cell-recognition also requires CD14 and TLR6, that may act synergistically with TLR2 and function as co-receptors for secreted microbial products. It also seems that neither TLR1 nor TLR4 participate in GBS recognition. Further downstream signaling pathways are by both MyD88 –dependent and –independent pathways. Whereas the former is necessary for NF-κB expression, bacterial uptake depends on the later mechanism. In addition, Grampositive bacteria can also trigger cytosolic PRRs, including NOD1/2 and the NALP1 inflammasome, both activated by PG.
Reference: MARÍA DE LA CRUZ DOMÍNGUEZ PUNARO. STUDIES ON THE EXAGGERATED INFLAMMATORY RESPONSE CAUSED BY STREPTOCOCCUS SUIS AT SYSTEMIC AND CENTRAL NERVOUS SYSTEM LEVELS