The fate and importance of Toll like receptors in a mammalian system . The slides include the signaling cascade after the activation of TLRS and the consequences on the intracellular signaling pathways that it follows

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Consequences of
Toll Like Receptors
Presented by: Raghav Worah
Department of Biochemistry and Biotechnology
St. Xavier’s College, Ahmedabad
and its Involvement in a plethora of other signaling cascade after its activation

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Table of Contents
• Introduction
• Initiation of Signaling
cascade
• Outcomes from the intracellular
signaling
• A perspective

3. Toll like receptors are a class of proteins
that play a key role in the innate immune
system.
They are present on the surface of the
cell (like macrophages) and mediate the
release of cytokines and chemokines.
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• Toll like receptors are single pass membrane spanning receptors that
recognizes conserved molecules derived from the microbes
1: Introduction:
Toll like receptors are considered
to be extracellular but there are
also TLRs which are intracellular
Image courtesy: Frontiers.org

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In a mammalian system there are 10genes that would give rise to 10 types of TLRs.
• Each type of TLR would bind to a particular adaptor molecules to initiate the intracellular signaling
cascade.
• Its not just the macrophages ,the dendritic cells or the B cells that are associated with TLR. Even
the non-immune cells such as the fibroblasts and epithelial cells would have TLRs.
TLRs can recognize several molecules that are associated with a foreign body.
• Lipoteichoic acid of gram positive bacteria
• Lipopolysaccharide of gram negative bacteria
• A double stranded RNA
• Unmethylated CpG residues of bacterial DNA

5. • It is in the presence of a ligand that induces dimerization of the TLR ectodomains and it
brings the cytoplasmic tail in the close proximity to initiate intra-celluar signalling
2: Initiation of Signaling cascade:
Different types of
TLR receptors
would interact with
different adaptor
molecules.
These adaptor
molecules are
MyD88, MAL,
TRIF, TRAM.
• Different TLRs would recognize different adaptor molecules, these recognition of
adaptor molecules is either done by a single TLR or hetero-dimeric TLR.
Image Courtesy: Nature

6. • Stimulation of TLRs triggers the association of MyD88 which recruits
IRAK4 and then this IRAK4 recruits IRAK1.
• IRAK4 induces phosphorylation of IRAK1. TRAF6 is also recruited to the
receptor complex, by associating with phosphorylated IRAK1.
• Phosphorylated IRAK1 and TRAF6 then dissociate from the receptor and
form a complex with TAK1 and TAB1
• IRAK1 is degraded at the plasma membrane, and the remaining complex
translocates to the cytosol, where it associates with the ubiquitin ligases
UBC13 and UEV1A . This leads to the ubiquitylation of TRAF6, which
induces the activation of TAK1.
• TAK1, in turn, phosphorylates both mitogen-activated protein (MAP)
kinases and the IKK complex consists of IKK-α, IKK-β and IKK-γ.
• The IKK complex then phosphorylates IκB, which leads to its ubiquitylation
and subsequent degradation. This allows NF-κB to translocateto the
nucleus and induce the expression of its target genes
Image Courtesy: Fronteirs.org

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3: Outcomes from the intracellular signaling:
• The cytokines and the chemokines produced by the macrophages upon activation of NF-kB by
TLR is not only responsible for innate immunity but it is also involved with IL-12 that confers
adaptive immunity.
The chemokines that are produced attracts neutrophiles and other immune cells at the site of infection.
• The cell surface proteins B7.1 and B7.2 get activated due to TLR signaling and are responsible
for adaptive immunity.
• The cosimulatory molecule with antigenic B7.1 and B7.2, alongwith MHC molecules activates
CD4+ T cells of the immune system
• TNF a is also produced (involvement of TLR 4 signaling) that stimulates the APCs to migrate to
the lymphatic system and there they would help in the activation of naïve T cells
.

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• Toll like receptors are also involved in actin polymerization, angiogenesis and induction of apoptosis
• They are also involved in iso-type switching.
TLR2 and TLR 5 are involved in
induction of apoptosis and the adaptor
molecule is MYD88 that would activate
the pro caspases and intiate the
apoptotic cascade
Image Courtesy: ReseachGate

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• Toll like receptors signaling is used as a potential therapeutic target in
colorectal cancer and atherosclerosis.
• Toll like receptors are involved in regenerative myogeneis.
• Due to the presence of Toll like receptors there is microbial stimulation that
would induce diverse metabolic programmes in human monocytes.
• Toll like receptor 4 is involved in the signaling cascade of neuropyschiatric
disease.
4: A perspective

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References
Shizuo, Takeda.K; (2004)Toll-like Receptor Signaling. Nature Reviews. Immunology p.
499–511. https://www.nature.com/articles/4401850#citeas
Hopkins, P. A.; Sriskandan, S. Mammalian Toll-like receptors: to immunity and beyond
(2005) Clinical and Experimental Immunology, 140(3), pp.395-407.
https://academic.oup.com/cei/article/140/3/395/6440532?login=false
Gao. W; Xiaong. Y; Qiang. Li; Yang.H: (2017) Inhibition of Toll-Like receptors as a
promising therapy for inflammatory diseases: Journey from molecular to nanotherapeutics.
Frontiers Physiology. https://www.frontiersin.org/articles/10.3389/fphys.2017.00508/full
Zayat. E; Salwa. R;Toll-like (2019) Receptors Activation, Signaling, and Targeting: An
Overview.” Bulletin of the National Research Centre, vol. 43.
https://bnrc.springeropen.com/articles/10.1186/s42269-019-0227-2#citeas

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Thank You