Introductory Chapter: Toll-Like Receptors

*Amene Saghazadeh and Nima Rezaei*

### **1. The first line of defense is filled with a variety of pattern recognition receptors**

Pattern recognition receptors (PRRs), which are germ line-encoded receptors, probably provided the host with the best possible innate property to identify "nonself" invaders from both exogenous and endogenous sources. PRRs can discriminate self-microorganisms and molecules from nonself ones through recognizing conserved parts of microorganisms—which are known as microorganismassociated molecular patterns (MAMPs). If it is nonself, then they will direct the induction of inflammatory responses. In addition, PRRs allow the innate immunity to identify endogenous danger signals—which are released by stressed, damaged, or dying cells and known as damage-associated molecular patterns (DAMPs)—and thereby help in initiation of sterile inflammation. In this manner, PRRs participate in the clearance of invading pathogens by regulating infectious inflammation and contribute to tissue repair and regeneration in addition to elimination of autoimmunity and tumorigenesis by regulating sterile inflammatory processes.

They display three types of localization. Toll-like receptors (TLRs) are a kind of PRRs located in the membrane along with C-type lectin receptors. Also, nucleotide oligomerization domain (NOD)-like receptors (NLR) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) are found in the nucleus and contribute to recognition of intracellular microorganisms. Finally, there are some proteins that their synthesis occurs in the cells and can be used as receptors by various microorganisms. TLRs—which are the subject of this book—were the first discovered family of PRRs.

#### **2. Toll-like receptors**

They exist in mammals and insects and mediate actions essential to achieve control over immune homeostasis. The major cells expressing TLRs are antigenpresenting cells (APCs). Activation of TLRs in APCs can affect maturation of these cells and T helper 1 (Th1) cell differentiation for processing more specific immune mechanisms [1]. However, different cell types of the body have the capacity to induce the expression of TLRs, allowing them to carry TLR-mediated signaling pathways and production of inflammatory mediators and type I interferons (IFN). When handling a number of immune and inflammatory pathways, TLRs are able to have a role in the induction of innate immune responses and to link the innate immunity with the acquired immunity. Interfering with TLR function leads inevitably to immunological anomalies seen in common conditions ranging from immunodeficiency and infection to allergy, autoimmunity, cancer and more generally to diseases of many organ systems including the central

nervous system, lung, cardiovascular system, kidney, skin, and gastrointestinal system which are rooted in chronic inflammation. This has been fuel for advances in prophylactic and therapeutic applications of TLRs, especially in the last two decades.

#### **2.1 Cells expressing TLRs**

TLRs are found on the different cells of both the innate and adaptive immunity. Notably, they are expressed by nonimmune cells in the body. Normal nontransformed cells, such as endothelial cells, epithelial cells, fibroblasts, glial cells, neurons, and neural progenitor cells, as well as transformed cells of the body, i.e., cancer cells, may mediate the expression of TLRs. In humans, intestinal epithelial cells (IECs) are the main nonimmune source of TLRs. It is not aimless—there is evidence that the recognition of commensal bacteria by TLRs is required for the regulation of intestinal homeostasis [2].

### **2.2 Structure of TLRs**

To date, 13 TLRs have been described in mammals, 10 of which are present in humans (TLR1–10). Each TLR consists of three domains: intracellular, transmembrane, and extracellular. The intracellular or cytoplasmic domain is conserved between TLRs and interleukin-1 family of receptors (IL-1R). It is, thus, referred to as the Toll-IL-1R (TIR) domain. The extracellular domain includes tandem leucinerich repeats (LRRs), which with their curved surface appear to determine which ligand(s) a TLR can bind. The transmembrane location of TLRs makes them very suitable to transmit signals from the extracellular matrix to the cytoplasm (signal transduction).

## **2.3 Cellular distribution of TLRs**

TLRs are located either within the cell membrane or in the intracellular compartments including the endoplasmic reticulum, endosomes, lysosomes, and endolysosomes:

Cell-membrane TLRs: TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 Intracellular TLRs: TLR3, TLR7, TLR8, and TLR9

Like other receptors, TLRs act in relation to their cellular distribution. Cellmembrane TLRs are eligible for identification of membrane components of microorganisms, e.g., lipids, proteins, and lipoproteins, while intracellular TLRs are for identification of nuclear components of microorganisms, i.e., nucleic acids.

### **2.4 Ligands of TLRs**

In general, MAMPs are divided into three: glycans, proteins, and nucleic acids. Particularly, ligands that participate in host-pathogen interactions vary based on the pathogen identity and include:

Bacteria: lipoteichoic acid, peptidoglycan, lipoprotein/lipopeptides, deoxyribonucleic acid (DNA), flagellin, and lipopolysaccharide Viruses: coat proteins and nucleic acids Parasites: glycosylphosphatidylinositol (GPI) protein-membrane anchors Yeast: zymosan

**3**

**Cellular distribution [3]**

> TLR1

Cell surface

Monocyte/macrophage

Neutrophils

MDCs PDCs

> TLR2

Cell surface

Monocyte/macrophage

×

×

Gastric

Lipoprotein/lipopeptides

HA (MV)

Zymosan

GIPLs (*T. cruzi*)

(*Saccharomyces*)

PLM (*C.* 

*albicans*)

SVP (HSV,

CMV)

(GPB, mycoplasma,

mycobacteria,

Spirochetes)

Peptidoglycan (GPB)

Lipoteichoic acid (GPB)

PSM (*S. epidermidis*)

HKB (*L. monocytogenes*)

Porins (*Neisseria*)

Soluble factors (*N.* 

cancer

Colorectal

cancer

Ovarian

cancer

Cervical

cancer

Lung

cancer

Melanoma

*meningitidis*)

Atypical LPS (*L.* 

*interrogans*, *P. gingivalis*)

OmpA (*K. pneumoniae*)

Glycolipids (*T.* 

*maltophilum*)

LAM (mycobacteria)

Brain

cancer

Breast

cancer

Liver

cancer

Laryngeal

cancer

Pancreatic

cancer

Neutrophils

MDCs

Mast cells

B cells

×

×

Lipopeptides Soluble factors (*N. meningitidis*)

×

×

×

**Expressing cell type**

**Innate immune cells**

**Adaptive immune cells**

**IECs**

**Cancer cells**

**Bacteria Ligand (origin)**

**Viruses Ligand (origin)**

**Fungi Ligand (origin)**

**Protozoa Ligand (origin)**

**Exogenous ligands [4]**

*Introductory Chapter: Toll-Like Receptors DOI: http://dx.doi.org/10.5772/intechopen.88493*


#### *Introductory Chapter: Toll-Like Receptors DOI: http://dx.doi.org/10.5772/intechopen.88493*

*Toll-like Receptors*

**2.1 Cells expressing TLRs**

**2.2 Structure of TLRs**

transduction).

endolysosomes:

**2.4 Ligands of TLRs**

Yeast: zymosan

the pathogen identity and include:

regulation of intestinal homeostasis [2].

**2.3 Cellular distribution of TLRs**

decades.

nervous system, lung, cardiovascular system, kidney, skin, and gastrointestinal system which are rooted in chronic inflammation. This has been fuel for advances in prophylactic and therapeutic applications of TLRs, especially in the last two

TLRs are found on the different cells of both the innate and adaptive immunity. Notably, they are expressed by nonimmune cells in the body. Normal nontransformed cells, such as endothelial cells, epithelial cells, fibroblasts, glial cells, neurons, and neural progenitor cells, as well as transformed cells of the body, i.e., cancer cells, may mediate the expression of TLRs. In humans, intestinal epithelial cells (IECs) are the main nonimmune source of TLRs. It is not aimless—there is evidence that the recognition of commensal bacteria by TLRs is required for the

To date, 13 TLRs have been described in mammals, 10 of which are present in humans (TLR1–10). Each TLR consists of three domains: intracellular, transmembrane, and extracellular. The intracellular or cytoplasmic domain is conserved between TLRs and interleukin-1 family of receptors (IL-1R). It is, thus, referred to as the Toll-IL-1R (TIR) domain. The extracellular domain includes tandem leucinerich repeats (LRRs), which with their curved surface appear to determine which ligand(s) a TLR can bind. The transmembrane location of TLRs makes them very suitable to transmit signals from the extracellular matrix to the cytoplasm (signal

TLRs are located either within the cell membrane or in the intracellular compartments including the endoplasmic reticulum, endosomes, lysosomes, and

Like other receptors, TLRs act in relation to their cellular distribution. Cellmembrane TLRs are eligible for identification of membrane components of microorganisms, e.g., lipids, proteins, and lipoproteins, while intracellular TLRs are for identification of nuclear components of microorganisms, i.e., nucleic acids.

In general, MAMPs are divided into three: glycans, proteins, and nucleic acids. Particularly, ligands that participate in host-pathogen interactions vary based on

Bacteria: lipoteichoic acid, peptidoglycan, lipoprotein/lipopeptides, deoxyribo-

Parasites: glycosylphosphatidylinositol (GPI) protein-membrane anchors

Cell-membrane TLRs: TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10

Intracellular TLRs: TLR3, TLR7, TLR8, and TLR9

nucleic acid (DNA), flagellin, and lipopolysaccharide

Viruses: coat proteins and nucleic acids

**2**


**5**

**Cellular distribution [3]**

> TLR4

Cell surface

Monocyte/macrophage

Neutrophils

MDCs Mast cells

B cells

Gastric

LPS (GNB)

Hsp60 (*C. pneumonia*)

cancer

Colorectal

cancer

Ovarian

cancer

Cervical

cancer

Lung

cancer

Prostate

cancer

Melanoma

Brain

cancer

Breast

cancer

Liver

cancer

Laryngeal

cancer

TLR5

Cell surface

Monocyte/macrophage

×

Breast

Flagellin (flagellated

×

×

×

cancer

bacteria)

Gastric

cancer

Colorectal

cancer

Ovarian

cancer

Cervical

cancer

Neutrophils

MDCs

**Expressing cell type**

**Innate immune cells**

**Adaptive immune cells**

**IECs**

**Cancer cells**

**Bacteria Ligand (origin)**

**Viruses Ligand (origin)**

**Fungi Ligand (origin)**

**Protozoa Ligand (origin)**

Envelope

×

proteins (RSV

and MMTV)

Fusion protein

(RSV)

GIPLs (*T. cruzi*)

**Exogenous ligands [4]**

*Introductory Chapter: Toll-Like Receptors DOI: http://dx.doi.org/10.5772/intechopen.88493*


*Introductory Chapter: Toll-Like Receptors DOI: http://dx.doi.org/10.5772/intechopen.88493*

*Toll-like Receptors*

**4**

**Cellular** 

**Expressing cell type**

**Innate immune cells**

**Adaptive** 

**IECs**

**Cancer** 

**Bacteria**

**Viruses**

**Fungi**

**Protozoa**

**Ligand (origin)**

**Ligand (origin)**

**Ligand (origin)**

dsRNA

×

×

**Ligand (origin)**

**cells**

**immune cells**

B cells

×

Colorectal

×

cancer

Ovarian

cancer

Cervical

cancer

Lung

cancer

Melanoma

Breast

cancer

Liver

cancer

Laryngeal

cancer

T cells

**Exogenous ligands [4]**

**distribution** 

**[3]**

TLR3

Intracellular

MDCs

endosomal

compartment


**7**

**Cellular distribution [3]**

> TLR10

Cell surface

Monocyte/macrophage

B cells

× *GPB, gram-positive bacteria; IEC, intestinal epithelial cells; LPS, lipopolysaccharides; OmpA, outer membrane protein A; HSV, herpes simplex virus; CMV, cytomegalovirus; GIPLs, glycoinositolphospholipids; dsRNA, double-stranded RNA; GNB, gram-negative bacteria; DCs, dendritic cells; MMTV, mouse mammary tumor virus; RSV, respiratory syncytial virus; ssRNA, single-*

*stranded RNA; MDS, myeloid dendritic cells; N. meningitides, Neisseria meningitides; PDCs, plasmacytoid dendritic cells; S. epidermidis, Staphylococcus epidermidis; PSM, phenol-soluble modulin; HKB, heat-killed bacteria; L. monocytogenes, Listeria monocytogenes; L. interrogans, Leptospira interrogans; P. gingivalis, Porphyromonas gingivalis; K. pneumoniae, Klebsiella pneumoniae; T. maltophilum, Treponema maltophilum; LAM, lipoarabinomannan; PLM, phospholipomannan; T. cruzi, Trypanosoma cruzi; C. albicans, Candida albicans; HA, hemagglutinin; MV, measles virus; SVP, structural viral proteins; C. pneumonia, Chlamydia pneumonia; HLSF, heat-labile soluble factor.*

**Table 1.** *Toll-like receptors: cellular distribution, expressing cell types, and exogenous ligands.*

**Expressing cell type**

**Innate immune cells**

**Adaptive immune cells**

**IECs**

**Cancer cells**

**Bacteria Ligand (origin)**

**Viruses Ligand (origin)**

**Fungi Ligand (origin)**

**Protozoa Ligand (origin)**

Triacylated lipopeptides

×

×

×

**Exogenous ligands [4]**

*Introductory Chapter: Toll-Like Receptors DOI: http://dx.doi.org/10.5772/intechopen.88493*


**Table 1.** *Toll-like receptors: cellular distribution, expressing cell types, and exogenous ligands.*

#### *Introductory Chapter: Toll-Like Receptors DOI: http://dx.doi.org/10.5772/intechopen.88493*

*Toll-like Receptors*

**6**

**Cellular** 

**Expressing cell type**

**Innate immune cells**

**Adaptive** 

**IECs**

**Cancer** 

**Bacteria**

**Viruses**

**Fungi**

**Protozoa**

**Ligand (origin)**

**Ligand (origin)**

Zymosan

(*Saccharomyces*)

**Ligand (origin)**

**Ligand (origin)**

**cells**

**immune cells**

**Exogenous ligands [4]**

**distribution** 

**[3]**

TLR6

Cell surface

Monocyte/macrophage

B cells

×

Liver

Diacyl lipopeptides

(mycoplasma)

Lipoteichoic acid (GPB)

PSM (*S. epidermidis*)

HLSF (group B

streptococcus)

cancer

Neutrophils Mast cells

MDCs

PDCs

TLR7

Intracellular

Monocyte/macrophage

B cells

×

×

×

ssRNA

×

×

endosomal

Neutrophils

compartment

TLR8

Intracellular

Monocyte/macrophage

×

×

×

ssRNA

×

×

endosomal

Neutrophils

MDCs

Mast cells

compartment

TLR9

Intracellular

Monocyte/macrophage

B cells

×

Gastric

Unmethylated CpG DNA

Unmethylated

×

Hemozoin

(*Plasmodium*)

CpG DNA

cancer

Colorectal

cancer

Cervical

cancer

Lung

cancer

Prostate

cancer

Breast

cancer

Liver

cancer

T cells

endosomal

Neutrophils

compartment

PDCs

DCs

TLRs have been reported to bind endogenous and exogenous ligands. There is a wide range of microorganisms including bacteria, viruses, protozoa and helminth parasites, and fungi that TLRs can defend against. **Table 1** provides an overview of ligands and associated pathogens that interact with TLRs. However, below are representative examples for MAMPs that can be recognized by TLRs:

TLR1: lipoproteins TLR2: lipoteichoic acid, peptidoglycan, lipoproteins, and zymosan TLR3: viral dsRNA TLR4: lipopolysaccharide, viral envelope protein, and viral fusion protein TLR5: flagellin TLR6: lipoteichoic acid, lipoproteins, and zymosan TLR7 and TLR8: viral ssRNA, synthetic antiviral compounds (imidazoquinolines) TLR9: bacterial and viral DNA TLR10: triacylated lipopeptides

Endogenous ligands that can be recognized by TLRs are numerous but mainly include extracellular matrix components, high-mobility group box 1, heat shock proteins (HSP), tenascin-C, cardiac myosin, and S100 proteins (for review see [5]).

### **3. TLR-mediated signaling pathways: network of adaptor molecules and transcription factors**

Ligand recognition by TLRs involves the recruitment of different TIR domaincontaining adaptor proteins. The types of adaptor proteins they use at least in part explain distinct functions of TLRs.

To date, there have been four adaptor proteins found to interact with specific TLRs (**Table 2**). Myeloid differentiation primary response 88 (MyD88) was the first of its kind. It is an intracytoplasmic adaptor molecule that consists of a C-terminal TIR domain and an N-terminal death domain. Its TIR domain—which is fundamental to ligand site recognition—can interact with all TLRs with the exception of TLR3. Recruitment of MyD88 by TLRs initiates the cascades of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) that result in the production of inflammatory cytokines.

In this context, TIR-domain-containing adapter-inducing interferon-β (TRIF) is another adaptor protein. TLR3 and also TLR4 can act as a trigger for TRIFdependent signaling. This signaling then utilizes transcription factors NF-κB and interferon regulatory factor 3 (IRF3) to produce inflammatory cytokines and type I IFN.

Toll-interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP) and TRIF-related adaptor molecule (TRAM) are last two remaining TIR domain-containing adaptor proteins. They are specialized for directing other adaptors to specific TLRs and thus are referred to as sorting adaptors. TIRAP serves as the sorting adaptor for MyD88 and facilitates its recruitment to TLR1, TLR2, TLR4, and TLR6, while TRAM is merely involved in the interaction between TRIF and TLR4.

In this manner, the discussion on signaling pathways mediated by TLRs is commonly held in MyD88-dependent and TRIF-dependent settings (for review see [7]). **Figure 1** is a schematic diagram of TLR location and pathways.

**9**

**Figure 1.**

**Table 2.**

**3.1 TLRs and different disease entities**

*Toll-like receptor (TLR) location and signaling pathways.*

Studies in mice have demonstrated that TLR signaling change underlies a range

of pathologies. Supporting this, human studies propose that single nucleotide polymorphisms (SNPs) that alter—whether upregulated or downregulated—TLR

signaling may predispose to or protect from development of diseases [8].

*Introductory Chapter: Toll-Like Receptors DOI: http://dx.doi.org/10.5772/intechopen.88493*

> **MyD88 dependent signaling**

**Signaling adaptor(s) Transcription** 

**Sorting adaptor**

and TRAM

TLR1 × TIRAP NF-κB × TLR2 × TIRAP NF-κB ×

TLR5 × × NF-κB × TLR6 × TIRAP NF-κB × TLR7 × × NF-κB and IRF7 TLR8 × × NF-κB and IRF7 TLR9 × × NF-κB and IRF7

**TRIFdependent signaling**

TLR4 TIRAP

*Toll-like receptor: signaling pathways and products [6].*

TLR3 × × NF-κB, IRF3,

**factor(s)**

and IRF7

NF-κB, IRF3, and IRF7

**Products**

**Inflammatory cytokines**

**Type I IFN**

*Introductory Chapter: Toll-Like Receptors DOI: http://dx.doi.org/10.5772/intechopen.88493*


#### **Table 2.**

*Toll-like Receptors*

TLR1: lipoproteins

TLR3: viral dsRNA

(imidazoquinolines)

**transcription factors**

explain distinct functions of TLRs.

tion of inflammatory cytokines.

between TRIF and TLR4.

TLR9: bacterial and viral DNA TLR10: triacylated lipopeptides

TLR5: flagellin

review see [5]).

TLRs have been reported to bind endogenous and exogenous ligands. There is a wide range of microorganisms including bacteria, viruses, protozoa and helminth parasites, and fungi that TLRs can defend against. **Table 1** provides an overview of ligands and associated pathogens that interact with TLRs. However, below are

representative examples for MAMPs that can be recognized by TLRs:

TLR7 and TLR8: viral ssRNA, synthetic antiviral compounds

TLR6: lipoteichoic acid, lipoproteins, and zymosan

TLR2: lipoteichoic acid, peptidoglycan, lipoproteins, and zymosan

TLR4: lipopolysaccharide, viral envelope protein, and viral fusion protein

Endogenous ligands that can be recognized by TLRs are numerous but mainly include extracellular matrix components, high-mobility group box 1, heat shock proteins (HSP), tenascin-C, cardiac myosin, and S100 proteins (for

**3. TLR-mediated signaling pathways: network of adaptor molecules and** 

Ligand recognition by TLRs involves the recruitment of different TIR domaincontaining adaptor proteins. The types of adaptor proteins they use at least in part

To date, there have been four adaptor proteins found to interact with specific TLRs (**Table 2**). Myeloid differentiation primary response 88 (MyD88) was the first of its kind. It is an intracytoplasmic adaptor molecule that consists of a C-terminal TIR domain and an N-terminal death domain. Its TIR domain—which is fundamental to ligand site recognition—can interact with all TLRs with the exception of TLR3. Recruitment of MyD88 by TLRs initiates the cascades of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) that result in the produc-

In this context, TIR-domain-containing adapter-inducing interferon-β (TRIF)

In this manner, the discussion on signaling pathways mediated by TLRs is commonly held in MyD88-dependent and TRIF-dependent settings (for review see [7]).

**Figure 1** is a schematic diagram of TLR location and pathways.

is another adaptor protein. TLR3 and also TLR4 can act as a trigger for TRIFdependent signaling. This signaling then utilizes transcription factors NF-κB and interferon regulatory factor 3 (IRF3) to produce inflammatory cytokines and type

Toll-interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP) and TRIF-related adaptor molecule (TRAM) are last two remaining TIR domain-containing adaptor proteins. They are specialized for directing other adaptors to specific TLRs and thus are referred to as sorting adaptors. TIRAP serves as the sorting adaptor for MyD88 and facilitates its recruitment to TLR1, TLR2, TLR4, and TLR6, while TRAM is merely involved in the interaction

**8**

I IFN.

*Toll-like receptor: signaling pathways and products [6].*

**Figure 1.**

*Toll-like receptor (TLR) location and signaling pathways.*

#### **3.1 TLRs and different disease entities**

Studies in mice have demonstrated that TLR signaling change underlies a range of pathologies. Supporting this, human studies propose that single nucleotide polymorphisms (SNPs) that alter—whether upregulated or downregulated—TLR signaling may predispose to or protect from development of diseases [8].

#### **3.2 Autoimmunity**

All 10 TLRs that are present in humans (except to TLR5) have been associated with autoimmune and inflammatory diseases including arthritis, systemic lupus erythematosus, scleroderma, and Sjogren's syndrome [9]. There are potential opposing views on involvement of TLRs in autoimmunity.

Autoimmunity is referred to as conditions where the immune system is fighting against the body itself by production of antibodies, the so-called autoantibodies, against self molecules, the so-called autoantigens. Autoantibodies bind to autoantigens and form immune complexes. The cytokine interferon-alpha (IFNα) was first thought to have a pure white role of antiviral immunity. However, the observations of autoimmune features caused by the use of recombinant IFNα in patients with chronic viral infections have expanded the former function of IFNα far beyond antiviral immunity to autoantibody production and autoimmunity. A hypothesis is that immune complexes having nucleic acids can act as ligands for TLRs, thereby making the innate immune cells to induce more than wanted or unwanted responses. TLRs that can recognize nucleic acids, i.e., TLR7 and TLR9, and plasmacytoid dendritic cells (pDCs) that express these receptors and produce IFNα in response are of particular importance in this context [9]. In contrast, some TLRs have been reported to turn the knob in the opposite direction. When reviewing the role of TLRs in inflammatory arthritis, TLRs may stimulate osteoclastogenesis, and on the other side, there are TLRs that inhibit activation of osteoclasts and thus can prevent bone destruction [10].

#### **3.3 Brain diseases**

Different brain cells reveal the expression of TLRs:

Microglia express all TLRs. Neurons express TLR3, TLR7, TLR8, and TLR9. Astrocytes express TLR2, TLR3, and TLR9. Oligodendrocytes express TLR2 and TLR3.

The role of TLRs has been characterized in the normal central nervous system (CNS) as well as in disease states of the CNS. Experimental evidence suggests the possible role of TLR2 in neurogenesis, whereas TLR3 and TLR4 apparently act as downregulators of neurogenesis. Enhancement of hippocampal-dependent working memory in mice lacking TLR3 implicates this receptor as a negative regulator of cognitive functions as well. In bacterial infections of the brain and abscess formation, TLR2, TLR4, and TLR9 are essential to elicit immune responses. In the cases of viral meningitis, TLR3 and TLR9 engagement can help to localize infection and diminish neural injury as well. In parasite infections of the brain, TLR1, TLR2, and TLR9 show paradoxical effects they may worsen disease rather than clear parasites from the brain. Both models of neuronal injury and of spinal cord injury indicate a role for TLR2 and TLR4 in inducing neuronal death and axon and myelin damage. Finally, evidence points to the potential role that TLR2, TLR4, TLR5, TLR7, and TLR9 can play in preventing the accumulation of amyloid plaques and progression of Alzheimer's disease [11].

#### **3.4 Cardiovascular diseases**

Cardiac myocytes show the expression of TLR2, TLR3, TLR4, and TLR6. TLRs play paradoxical roles in different myocardial diseases. For example, TLR2 was

**11**

*Introductory Chapter: Toll-Like Receptors DOI: http://dx.doi.org/10.5772/intechopen.88493*

review see [12]).

injury [12].

**3.5 Infections**

care unit [13].

see [14]).

**3.6 Kidney diseases**

**3.7 Liver diseases**

shown to mediate apoptosis of cardiac myocytes induced by hydrogen peroxide and doxorubicin, while TLR4 attenuated apoptosis of cardiac myocytes. Targeting both TLR2 and TLR4 provided protection in septic cardiomyopathy. TLR4 blockade implied benefit to ischemia-reperfusion injury and cardiac hypertrophy as well (for

TLR4 is also said to be highly expressed in atherosclerotic lesions which inflammation is supposed to corporate in its nature. There are possible explanations which can be given to this fact. The oxidization of lipids as a way to form atherosclerotic lesions accompanies thermal stress through HSP production. Oxidized lipids and HSPs can act as ligands and upregulate MyD88-dependent TLR4 relevant to inflammatory cytokine production. Another explanation is that TLR4 mediates recognition of *Chlamydia pneumoniae*, which in turn is closely related to atherosclerosis. In this manner, it would be understandable that individuals carrying Asp299Gly and Thr399Ile—which interfere with TLR4 function—develop less atherosclerotic vascular events, such as carotid stenosis, acute coronary events, acute myocardial infarction, diabetic neuropathy, and allograft rejection [13]. On the other hand, TLRs, in particular TLR2, TLR4, TLR7, and TLR9, by the aid of adenosine, can succeed in angiogenesis after myocardial

As described above, TLR4 is critical in recognizing LPS of gram-negative bacteria (GNB). People's reactions are different to LPS inhalation and range from tolerance, i.e., no reaction, to strong asthma-like reactions. SNPs of human TLR4 gene, i.e., Asp299Gly and Thr399Ile, have been reported to affect the degree of reaction to LPS among healthy subjects and allergic asthmatic patients, development of septic shock by GNB, incidence of severe respiratory syncytial virus (RSV) bronchiolitis, risk of GNB colonization and of premature birth in pregnant women, and incidence of infections by GNB in patients on an intensive

Less is understood about the role of TLRs in kidney diseases. However, experimental evidence suggests that all TLRs are involved in sepsis and renal infections. Each TLR has its own associations with distinct renal diseases as well (for review

In the liver, TLR expression is observed on a variety of cells including Kupffer cells (TLR2, TLR3, TLR4, and TLR9), hepatocytes (all TLRs), hepatic stellate cells (TLR2, TLR4, and TLR9), biliary epithelial cells (TLR2, TLR3, TLR4, and TLR5), sinusoidal epithelial cells (TLR4), hepatic dendritic cells (TLR2, TLR4, TLR7, and TLR9), hepatic natural killer cells (TLR1, TLR2, TLR3, TLR4, TLR6, TLR7, and TLR9), and hepatic B cells (TLR2, TLR4, TLR7, and TLR9). Undoubtedly, such widely distrusted TLRs have been an important part of multiple liver diseases including infections of the liver by *L. monocytogenes*, and *S. typhimurium*, *P. falciparum*, hepatitis C virus, and hepatitis B virus, alcohol-induced liver diseases, nonalcoholic fatty liver disease, hepatic fibrosis, liver injury, liver regeneration, and hepatocellular carcinoma, and hepatic immune disorders (for review see [15]).

#### *Introductory Chapter: Toll-Like Receptors DOI: http://dx.doi.org/10.5772/intechopen.88493*

shown to mediate apoptosis of cardiac myocytes induced by hydrogen peroxide and doxorubicin, while TLR4 attenuated apoptosis of cardiac myocytes. Targeting both TLR2 and TLR4 provided protection in septic cardiomyopathy. TLR4 blockade implied benefit to ischemia-reperfusion injury and cardiac hypertrophy as well (for review see [12]).

TLR4 is also said to be highly expressed in atherosclerotic lesions which inflammation is supposed to corporate in its nature. There are possible explanations which can be given to this fact. The oxidization of lipids as a way to form atherosclerotic lesions accompanies thermal stress through HSP production. Oxidized lipids and HSPs can act as ligands and upregulate MyD88-dependent TLR4 relevant to inflammatory cytokine production. Another explanation is that TLR4 mediates recognition of *Chlamydia pneumoniae*, which in turn is closely related to atherosclerosis. In this manner, it would be understandable that individuals carrying Asp299Gly and Thr399Ile—which interfere with TLR4 function—develop less atherosclerotic vascular events, such as carotid stenosis, acute coronary events, acute myocardial infarction, diabetic neuropathy, and allograft rejection [13]. On the other hand, TLRs, in particular TLR2, TLR4, TLR7, and TLR9, by the aid of adenosine, can succeed in angiogenesis after myocardial injury [12].

### **3.5 Infections**

*Toll-like Receptors*

**3.2 Autoimmunity**

prevent bone destruction [10].

Microglia express all TLRs.

**3.4 Cardiovascular diseases**

**3.3 Brain diseases**

All 10 TLRs that are present in humans (except to TLR5) have been associated with autoimmune and inflammatory diseases including arthritis, systemic lupus erythematosus, scleroderma, and Sjogren's syndrome [9]. There are potential

Autoimmunity is referred to as conditions where the immune system is fighting against the body itself by production of antibodies, the so-called autoantibodies, against self molecules, the so-called autoantigens. Autoantibodies bind to autoantigens and form immune complexes. The cytokine interferon-alpha (IFNα) was first thought to have a pure white role of antiviral immunity. However, the observations of autoimmune features caused by the use of recombinant IFNα in patients with chronic viral infections have expanded the former function of IFNα far beyond antiviral immunity to autoantibody production and autoimmunity. A hypothesis is that immune complexes having nucleic acids can act as ligands for TLRs, thereby making the innate immune cells to induce more than wanted or unwanted responses. TLRs that can recognize nucleic acids, i.e., TLR7 and TLR9, and plasmacytoid dendritic cells (pDCs) that express these receptors and produce IFNα in response are of particular importance in this context [9]. In contrast, some TLRs have been reported to turn the knob in the opposite direction. When reviewing the role of TLRs in inflammatory arthritis, TLRs may stimulate osteoclastogenesis, and on the other side, there are TLRs that inhibit activation of osteoclasts and thus can

opposing views on involvement of TLRs in autoimmunity.

Different brain cells reveal the expression of TLRs:

of amyloid plaques and progression of Alzheimer's disease [11].

The role of TLRs has been characterized in the normal central nervous system (CNS) as well as in disease states of the CNS. Experimental evidence suggests the possible role of TLR2 in neurogenesis, whereas TLR3 and TLR4 apparently act as downregulators of neurogenesis. Enhancement of hippocampal-dependent working memory in mice lacking TLR3 implicates this receptor as a negative regulator of cognitive functions as well. In bacterial infections of the brain and abscess formation, TLR2, TLR4, and TLR9 are essential to elicit immune responses. In the cases of viral meningitis, TLR3 and TLR9 engagement can help to localize infection and diminish neural injury as well. In parasite infections of the brain, TLR1, TLR2, and TLR9 show paradoxical effects they may worsen disease rather than clear parasites from the brain. Both models of neuronal injury and of spinal cord injury indicate a role for TLR2 and TLR4 in inducing neuronal death and axon and myelin damage. Finally, evidence points to the potential role that TLR2, TLR4, TLR5, TLR7, and TLR9 can play in preventing the accumulation

Cardiac myocytes show the expression of TLR2, TLR3, TLR4, and TLR6. TLRs play paradoxical roles in different myocardial diseases. For example, TLR2 was

Neurons express TLR3, TLR7, TLR8, and TLR9. Astrocytes express TLR2, TLR3, and TLR9. Oligodendrocytes express TLR2 and TLR3.

**10**

As described above, TLR4 is critical in recognizing LPS of gram-negative bacteria (GNB). People's reactions are different to LPS inhalation and range from tolerance, i.e., no reaction, to strong asthma-like reactions. SNPs of human TLR4 gene, i.e., Asp299Gly and Thr399Ile, have been reported to affect the degree of reaction to LPS among healthy subjects and allergic asthmatic patients, development of septic shock by GNB, incidence of severe respiratory syncytial virus (RSV) bronchiolitis, risk of GNB colonization and of premature birth in pregnant women, and incidence of infections by GNB in patients on an intensive care unit [13].

#### **3.6 Kidney diseases**

Less is understood about the role of TLRs in kidney diseases. However, experimental evidence suggests that all TLRs are involved in sepsis and renal infections. Each TLR has its own associations with distinct renal diseases as well (for review see [14]).

#### **3.7 Liver diseases**

In the liver, TLR expression is observed on a variety of cells including Kupffer cells (TLR2, TLR3, TLR4, and TLR9), hepatocytes (all TLRs), hepatic stellate cells (TLR2, TLR4, and TLR9), biliary epithelial cells (TLR2, TLR3, TLR4, and TLR5), sinusoidal epithelial cells (TLR4), hepatic dendritic cells (TLR2, TLR4, TLR7, and TLR9), hepatic natural killer cells (TLR1, TLR2, TLR3, TLR4, TLR6, TLR7, and TLR9), and hepatic B cells (TLR2, TLR4, TLR7, and TLR9). Undoubtedly, such widely distrusted TLRs have been an important part of multiple liver diseases including infections of the liver by *L. monocytogenes*, and *S. typhimurium*, *P. falciparum*, hepatitis C virus, and hepatitis B virus, alcohol-induced liver diseases, nonalcoholic fatty liver disease, hepatic fibrosis, liver injury, liver regeneration, and hepatocellular carcinoma, and hepatic immune disorders (for review see [15]).
