Innate immune system provides the 1st line of defence, when a micro organism enters into the body. Innate immune system differentiates the self and the foreign microbes.
This immune system depends on pattern- recognition receptors which differentiate different pathogens.
Toll like receptors belong to a class of receptors known as pattern- recognition receptors (PRRs) which recognise pathogen- associated molecular patterns (PAMPs) when a pathogen enters and trigger the suitable immune responses by multiple mechanisms. (Takeda K 2003)
In mammalians 11 toll like receptors have been identified, which trigger immunological responses (Kitano 2006).
Different TLRs recognize specific microbial components patterns.
TLR2 identifies microbial lipopetides.TLR3 helps in recognizing viral Double Stranded RNA TLR4 acts as a receptor for LPS. Flagellin are recognised by TLR5. TLR6 and 1 work along with TLR2 to differentiate triacyl lipopeptides and diacyl lipopeptides. TLR7 and 8 recognize viral Single stranded RNA.
Figure : TLRs with their specific ligands (Akira 2005)
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TLRs activate inflammatory reactions by synthesising pro inflammatory cytokines which help in eliminating the pathogens which invade the cell. It also activates signals involved in the production of adaptive immune responses by controlling the function of dendritic cell (Iwasaki A 2004 Oct)
STRUCTURE OF TLRs :
TLRs are members of a superfamily of interleukin-1 receptors and are described as single transmembrane type. They possess extracellular region rich in leucine known as leucine-rich repeats (LRRs),a cystein rich region , TM domain and cytoplasmic TIR domain or Toll/interleukin 1 receptor domain. (Akira 2003 oct)
They are ligand specific,that is they recognize the structures of ligands or microbes of endogenous sources and exogenous sources.
The LRR domain helps in ligand binding and is involved in recognising different pathogens, TIR domain is associated to innate immunity and helps in protein- protein interaction, it is responsible for inducing signals in the cell, this domain has three motifs box1, 2, 3. Box 2 forms a loop which is important for proper signalling.
PRODUCTION OF PROINFLAMMATORY CYTOKINES IL-1:
TLRs detect PAMPs that include different nucleic acids, viral double - stranded RNA, proteins, lipoproteins, etc and trigger signalling pathway which causes increased expression of inflammatory gene and activate TLR/IL-1R signalling.
IL-1 is an effective pro-inflammatory cytokines.
In the signalling pathways which are activated by TIR domain, activates a TIR domain-containing adaptor protein MyD88, Kinases and transcription factors like NF-kappaB which were essential for initiation of inflammatory cytokines and activating TLR3 and TLR4 signalling pathways which results in production of type I interferon's (IFNs) (O'Neill 2000).
TLR3 is as exception, it doesn't use MyD88 for initializing signalling pathway. It only requires TRIF adaptor molecule.
TLR/IL-1R-induced pathways are classified into pathways, MyD88-dependent and MyD88-independent responses.
MyD88- dependent pathway
The expression of inflammatory cytokines via activation of NF-B , is controlled by MyD88-dependent signalling pathway.
Lipopolysaccharide (LPS) stimulates toll-like receptor 4 (TLR4) releasing pro-inflammatory cytokines which are essential to activate immune responses (Lu YC 2008 May). LPS it a compound present in gram negative bacteria outer membrane and belongs to PAMPs. LPS reacts with CD14 along with TLRs forming a complex which induces signal transduction pathways is enhanced by TIR-domain containing adaptor molecule MyD88 (myeloid differentiation factor 88 ). MYD88 interacts with its respective TIR domain. This interaction involves members of the family interleukin-1 receptor-associated kinase (IRAK1 , IRAKI 4) via interactions between the DDs (Death Domians) of MyD88 and IRAKs. When LPS stimulation takes place, TIRAP also interacts with TLR4 through a TIR-TIR interaction which is essential for MyD88-dependent signalling.
MyD88 and IRAK1/4 interactions result in the macromolecular complex formation on transforming growth factor- activated kinase 1( TAK1), this activates transcription factor NF-B. (Karsan 2005). TAK1 also activates MAPKs that is, Mitogen- Activated Protein Kinases, which helps in activating the transcription factor AP-1. Pro- inflammatory cytokines are produced due to this activation of NF- B and AP- 1.
Mice with deficient MyD88 in reaction to all TLR ligands, doesn't show the production of pro- inflammatory cytokines like TNF-α and IL-12p40. All TLRs require MyD88 for inflammatory cytokine production. (Akira 2005).
MyD88- INDEPENDENT SIGNALLING :
In macrophages which are MyD88- Deficient, inflammatory cytokines production is not observed but activation of NF-κB and JNK is seen delayed (Taro Kawai1 1999).
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TLR3 triggers MyD88-independent signalling pathway, it requires Toll/IL-1-receptor-domain-containing adaptor inducing interferon-β (TRIF adaptor). TRAM is specific for TLR4 signalling pathway. TLR4 has the ability to activate both MyD88 dependent and MYD88- Independent pathways. TRIF adaptor associates with TRAF3 and activates the non canonical IKKs TBK1 and IKK which results in activation of IRF3 and transcription of IFNand IFN-inducible genes.
MyD88 dependent and independent signalling pathways produce inflammatory cytokines using different mechanisms and different kinetics.
In the case of MyD88 dependent signalling, NF- κB is induced with faster kinetics than that of MyD88- Independent signalling pathway.
DAMAGE ASSOCIATED MOLECULAR PATTERNS (DAMPs)
Under sterile conditions (absence of pathogen ) TLRs regulate inflammation, by recognizing ligands with different chemical structures. (A Mencin 2009)
Ability to recognize chemically unrelated ligands by endogenous ligands, initiates the activation of TLRs
These endogenous ligands belong to a group of molecules called as damage associated molecular patterns (DAMPs) and are related to injuries and inflammations caused in the cells. These DAMP molecules represent danger signals which induce inflammatory responses
Most if the DAMPs are nuclear proteins or cytosolic proteins.
In normal conditions DAMPs molecules are intracellular and not recognized by immune system, when released extra cellularly under cellular stress or injury they provoke immune response. Different mechanisms like necrotic cell leakages, inactive precursors degradation are involved in releasing the DAMP molecules into the extracellular environment.
For the molecules of DAMPs the terms 'alarmins' and 'endokines '(endogenous molecules that signal tissue and cell damage) have be proposed. (Bianchi 2007)
Examples for DAMPs are High mobility group box 1 protein (HMGB-1) and S100 proteins. (Dirk Foell 2007) .
Increased levels of these DAMPs are associated with inflammatory diseases, autoimmune diseases, atherosclerosis and cancer.
DAMPs affect on toll like receptors.
Damage- Associated Molecular Pattern (DAMP) molecules are important for initiating of pro- inflammatory of innate immunity.
DAMPs engage with TLRs as endogenous TLR ligands which are produced from dying cells. (Seki E 2008)
TLRs have an important role in the innate immune system that is initiated by DAMPs. TLRs connect with endogenous DAMPs and activate pro inflammatory signalling pathway that leads to the production of cytokines and endogenous danger signals.
Liver is subjected to injuries and dysfunction followed by ischemia- reperfusion, leading to the organ damage. Liver is targeted by bacterial PAMPs and by several DAMPs leading to injuries. This process causes activation of immune system and production of pro inflammatory responses. It has been proved that Toll like receptors play an important role in production of inflammatory response in liver diseases, by alerting innate immune system.
These toll like receptors are activated by DAMPs that are released during stress in the liver cells. DAMPs engage with TLRs through different mechanisms.
TLR4 is the main receptor that is activated by microbial inflammations and DAMPs. It has been reported that more than 20 DAMPs stimulate TLRs.
The major DAMPs that are involved in activating the TLRs are HMGB1, heat-shock proteins, surfactant protein, uric acid and extracellular matrix molecules like fibronectin, heparin sulphate, hyaluronan etc.
Studies proved that, TRLs activated by DAMPs sometimes release additional danger signals that function in paracrine or autocrine fashion causing organ damage and activating excessive innate immune response.
During liver injuries, exogenous and endogenous ligands of TLR4 are increased. This may be due to NASH or non-alcoholic steatohepatitis, immune disorders, alcohol,hepatitis virus, allograft rejection or due to drugs .
Figure : signalling of TLR4 in liver damage (Guo J 2010 Oct 21)
During this condition, HMGB1 and Hyaluronan are seen elevated and play an important role in liver damage.
HMGB1 is a nuclear protein which is expressed in almost all types of cells. HMGB1 binds to DNA and facilitate transcription in normal conditions but it is released under stress conditions like injury or infection, and promotes inflammation.
From activated macrophages HMGB1 is released in a delayed manner. DAMPs are released from the direct cellular damage due to oxidative stress which occurs during ischemia which are liberated from cell matrix. This is caused during cold ischemia.
During this condition, HMGB1 are released, HMGB1 is endogenous activator that activates TLR4 and activates cell signalling mediated by MyD88.
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TLR4 is activated by both exogenous like lipopolysaccharide (LPS) and endogenous ligands like HMGB1 producing pro-inflammatory cytokines and causing liver inflammation.
HMGB1 is released when LPS- induced TLR4 activation occurs, binds to LPS and carries it to TLR4 causing NF- κB activation, leading to inflammation. It is proved using ultrapure recombinant HMGB1 that HMGB1 doesn't bind to TLR4, but binds to RANGE to produce responses. HMGB1 has the capability to activate TLR4 in warm hepatic I/R, later on TLR4 activation regulates and releases HMGB1.
This proves that though HMGB1 activates TLR4, its release also depends on TLR4 itself.
Expression of IRF1 also effects the release of HMGB1 damage signals.. IRF1 is downstream of TRL4 activation.
MyD88 and TRIF signaling cascades are both included in TLR4 signilling pathways. But liver damage is independent of MyD88 signalling.
Figure : Role of TLR4 in hepatic I/R injury. (John Evankovich 2010)