There are 10 TLRs Many of them have the same intracellular s

There are 10 TLR\'s. Many of them have the same intracellular signaling cascade. Why wouldn\'t they all have the same signaling cascade leading to the same response? In your answer please include concepts about pathogens bound and proteins involved in the signaling cascade. (essay question, please help this worth 6 points for an immunology course quiz queston!)

Solution

Answer:

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors usually expressed in sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10.

The ability of immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of Immune receptors called toll-like receptors (TLRs) that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, and fibroblasts).
TLRs have been suspected of binding to host molecules including fibrinogen (involved in blood clotting), heat shock proteins (HSPs), HMGB1, extracellular matrix components and self DNA.
Different TLRs can recognize different antigens as listed below.

TLR 1: bacterial lipoprotein and peptidoglycans

TLR 2: bacterial peptidoglycans

TLR 3: double-stranded RNA

TLR 4: lipopolysaccharides

TLR 5: bacterial flagella

TLR 6: bacterial lipoprotein

TLR 7: single-stranded RNA, bacterial and viral

TLR 8: single-stranded RNA, bacterial and viral, phagocytized bacterial RNA.[30]

TLR 9: CpG DNA

TLR 10: unknown

TLRs are believed to function as dimers. Though most TLRs appear to function as homodimers, TLR2 forms heterodimers with TLR1 or TLR6, each dimer having a different ligand specificity. TLRs may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4\'s recognition of LPS, which requires MD-2. CD14 and LPS-Binding Protein (LBP) are known to facilitate the presentation of LPS to MD-2.

A set of endosomal TLRs comprising TLR3, TLR7, TLR8 and TLR9 recognize nucleic acid derived from viruses as well as endogenous nucleic acids in context of pathogenic events. Activation of these receptor leads to production of inflammatory cytokines as well as type I interferons (interferon type I) to help fighting viral infection.

TLR signaling consists of at least two distinct pathways: a MyD88-dependent pathway that leads to the production of inflammatory cytokines, and a MyD88-independent pathway associated with the stimulation of IFN- and the maturation of dendritic cells.
The MyD88-dependent pathway is common to all TLRs, except TLR3. Upon activation by PAMPs or DAMPs, TLRs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic TIR domain.
Adaptor proteins include the TIR-domain containing proteins, MyD88, TIRAP (TIR-associated protein), Mal (MyD88 adaptor-like protein), TRIF (TIR domain-containing adaptor protein-inducing IFN-) and TRAM (TRIF-related adaptor molecule).
Recruitment of MyD88 for instance, in turn recruits IRAK1 and IRAK4. IRAK4 subsequently activates IRAK1 by phosphorylation. Both IRAK1 and IRAK4 leave the MyD88-TLR complex and associate temporarily with TRAF6 leading to its ubiquitination. Bcl10 and MALT1 form oligomers that bind to TRAF6 promoting TRAF6 self-ubiquitination .
Recently, IRAK2 was shown to play a central role in TRAF6 ubiquitination. Following ubiquitination, TRAF6 forms a complex with TAB2/TAB3/TAK1 inducing TAK1 activation. TAK1 then couples to the IKK complex, which includes the scaffold protein NEMO, leading to the phosphorylation of IB and the subsequent nuclear localization of NF-B. Activation of NF-B triggers the the production of pro-inflammatory cytokines such as TNF-, IL-1 and IL-12.
TLR3, TLR7, TLR8 and TLR9 recognize viral nucleic acids and induce type I IFNs. The signaling mechanisms leading to the induction of type I IFNs differ depending on the TLR activated. They involve the interferon regulatory
factors, IRFs, a family of transcription factors known to play a critical role in antiviral defense, cell growth and immune regulation. Three IRFs (IRF3, IRF5 and IRF7) function as direct transducers of virus-mediated TLR signaling. TLR3 and TLR4 activate IRF3 and IRF7, while TLR7 and TLR8 activate IRF5 and IRF7.