TOLL-LIKE RECEPTORS.

TOLL-LIKE RECEPTORS

Toll-like receptors & Host-Pathogen Interaction
The discovery of TLRs created a huge excitement among immunologists. The study of these receptors and of the molecular events that unfold after they encounter a pathogen already starts to uncover new targets for pharmaceuticals that may enhance the protective activity of the body, bolster vaccines and give treatment to potentially deadly disorders. Thank you very much for listening. O’Neill, Luke A.J. “Immunity’s Early-Warning System”. Scientific American, Jan (2005),

Microbe products recognized
Conserved amoung microbes Known as pathogen-associated molecular patterns (PAMPs) PAMPs are recognized by plants as well as animals, meaning this innate response arose before the split Only vertebrates have evolved an adaptive immune response

Pattern Recognition Receptors (PRRs)
Toll-like receptors Natural history, function and regulation Mannose binding lectin (MBL) C-reactive protein Serum amyloid –P Functions of PRRs: Opsonization, activation of complement and coagulation cascades, phagocytosis, activation of pro-inflammatory signaling pathways, apoptosis

Nuesslein-Volhard: Drosophila Toll
Identified a protein she called “Toll” meaning “weird” Helps the Drosophila embryo to differentiate its top from its bottom (Neural tube development) 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Gay: Toll and Inner Part of Human IL-1R is Similar
Searching for proteins similar to Toll Shows cytoplasmic domain of Toll related to that of hIL-1R Identity extends for 135 aa Didn’t make sense Why does a protein involved in human inflammation look like one involved in fly neural tube development? 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Toll Molecular Structure
IL-1R Toll (will become TLRs) Ig-like domain Toll receptor has an extracellular region which contains leucine rich repeats motifs (LRRs) Toll receptor has a cytoplasmic tail which contains a Toll interleukin-1 (IL-1) receptor (TIR) domain LRRs TLR are TYPE 1 glycoproteins Cytoplasmic intracellular tail of TLRs shows a high homology with IL-1R family (known as the TIR domain), although the leucine rich repeat (LRR) contain extracellular domains are unrelated. TIR DOMAIN have a conserved region of aa in their cytoplasmic tails. The regions of homology comprise of three conserved boxes, which are crucial for signaling. Aa sequence conservation among TIR domains is generally 20-30% and these domains vary in size. It is responsible to initiate the intracellular signal. Leucine rich repeats (LRR) : tandem copies of the LRR motif. -Each repeat consists of aa – very different from IL-1R = has three immunoglobulin like domains. SWITCH : The concave surface of LRR domains is involved directly in the recognition of various pathogens. Remarkably, despite the conservation among LRR domains, different TLRs can recognize several structurally unrelated ligands. Box 1 TIR Domain Box 2 Box 3

Lemaitre: Flies use Toll to Defend from Fungi
Infected Tl-deficient adult flies with Aspergillus fumigatus All flies died after 2-3 days Flies use Toll to defend from fungi Thus, in Drosophila, Toll seems to be involved in embryonic development and adult immunity 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Lemaitre: Flies use Toll to Defend from Fungi
Drosophila has no adaptive immune system Therefore needs a rapid antimicrobial peptide response Two distinct pathways to activate antimicrobial peptide genes in adults Mutations in Toll pathway reduce survival after fungal infection 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Survival rate of adult Drosophila infected with Aspergillus fumigatus in Toll-

Medzhitov & Janeway: Human Toll Discovery
Ancient immune defence system based on the Toll signalling In insect, IL-1 receptor and the Toll protein are only similar in the segments within the cell They searched for human proteins that totally resemble to Toll 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Medzhitov & Janeway: Human Toll Discovery
Alignment of the sequences of human and Drosophila Toll proteins Homology over the entire length of the protein chains hToll gene most strongly expressed in Spleen and PBL (peripheral blood leukocytes) 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Rock: Identification of hTLR1-5
Identified 5 human Tolls, which they called Toll like receptors (TLRs) TLR4 same as Medzhitov’s human Toll 4 complete - 1 partial hTLR 3 Drosophila TLRs 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Poltorak: TLR4 Activated by LPS
Normal mice die of sepsis after being injected with LPS C3H/HeJ mice have defective response to LPS and survive Missense mutation affecting the cytoplasmic domain of Tlr4 Major breakthrough in the field of sepsis – molecular mechanism that underlies inflammation revealed 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Takeuchi: TLR6 discovery
Murine TLR6 expression detected in spleen, thymus, ovary and lung Alignment of a.a. sequence of cytoplasmic domains: TLR6 most similar to TLR1 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Chuang (2000): hTLR 7, 8 and 9 Reported the cloning and characterization of 3 hTLRs Ectodomain with multiple LRRs Cytoplasmic domain homologous to that of hIL-1R Longer ectodomain (higher MW) than hTLR1-6 mRNA expression: hTLR7 - lung, placenta and spleen hTLR8 – lung and PBL hTLR9 - spleen, lymph node, bone marrow and PBL 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Chuang (2001): hTLR10 Expression of hTLR10 in human tissues and cell lines Isolation of cDNA encoding hTLR10 Contains 811 aa, MW 94.6 kDA Architecture of hTLR10 same as in hTLR1-9 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

Chuang: hTLR10 Phylogenetic tree of hTLR: a.a. identity with hTLR1 (50%) and hTLR6 (49%) Only 30% with hTLR2 and 25% with the remaining ones 1985 1988 1989 1991 1996 1997 1998 1999 2000 2001

TLR Roles O’Neill, Luke A.J. “Immunity’s Early-Warning System”. Scientific American, Jan (2005),

TLR Cell Type Distribution
Receptor Cell Type TLR1 Ubiquitous TLR2 DCs, PMLs, and monocytes TLR3* DC and NK cells, upregulated on epithelial and endothelial cells TLR4 Macrophages, PMLs, DCs, ECs, but not on lymphocytes TLR5 Monocytes, immature DCs, epithelial, NK, and T cells TLR6 High expression in B cells, lower on monocytes and NK cells TLR7 B cells, plasmacytoid percursor DCs TLR8 Monocytes, low in NK cells and T cells TLR9 Plasmacytoid percursor DCs, B cells, macrophages, PMLs, NK cells, and microglial cells TLR10 B cells, plasmacytoid precursor DCs TLR11 Not Determined TLRs are expressed predominantly on cell types that are likely to be the first to encounter antigen Phagocytic cells such as macrophages, neutrophils, and dendritic cells exhibit the broadest repertoire and express the highest levels of TLRs, however, TLR expression is not restricted to these cell types. Although TLR expression patterns and levels in most cell and tissue types are still being defined, it appears that the majority of cells in the body express at least a subset of TLRs. TLR3 = There are conflicting reports regarding the expression of TLR3 in particular leukocyte populations. Some suggest that TLR3 is only expressed by DCs, while others find that TLR3 is expressed by T or NK cells. It has been shown that neutrophils express all TLRs except TLR-3. TLR3 = dsRNA (viral infection) although neutrophils aren’t usually associated with viral infections, they are associated with certain respiratory viral infections – therefore it is unclear by which mechanism neutrophils would directly recognize virally infected host cells. (Hayashi et al, 2003). Different cells types express varying combinations of TLRs, and TLR expression can be modulated based on the activation state of the cell. For exemple, resting mouse macrophages express TLR4, but extremely low levels of TLR2 and little or no TLR3. Upon activation, TLR4 is downregulated, and TLR2 and TLR3 are upregulated (Weiss et al, 2004). It was been proposed that sequential expression of TLR provides initial broad protection and later customizes to immune responses to different classes of microbes. – because macrophages are among the earliest cells to respond to infection, this system may represent one of the first ways in which the host tailors the immune response (David S. Weiss et al., 2004) GET PICTURE WITH THE DIFFERENT CELLS + different TLRs

Toll-Like Receptors and their Ligands
Ligand (PAMPs) Origin of Ligand TLR1 Triacyl lipopetides Soluble factors Bacteria and Mycobacteria Neisseria meningitidis TLR2 Heat Shock protein 70 Peptidoglycan Lipoprotein/lipopeptides HCV core and nonstructural 3 protein Host Gram-positive bacteria Various pathogens Hepatitis C Virus TLR3 Double-stranded RNA Viruses TLR4 Lipopolysaccharides Envelope protein Taxol Gram-negative bacteria Mouse mammary-tumor virus Plants TLR5 Flagellin Bacteria TLR6 Zymosan Lipoteichoic acid Diacyl lipopetides Fungi Mycoplasma TLR7 Single-stranded RNA (ssRNA) Imidazoquinoline Synthetic compounds TLR8 TLR9 CpG-containing DNA Bacteria, Malaria and Viruses TLR10 Not determined Not Determined TLR11 Profilin-like molecule Toxoplasma gondii To date, 11 TLRs have been identified in humans (12 have been identified in mice) Ex of the most studied ones : Bacterial products TLR2 = peptidoglycans & TLR4 = LPS & TLR9 = CpG motifs Viral products 4 classes of PAMPs = dsRNA, CpG DNA, ssRNA, and envelope glycoproteins. INTRO: SWITCH : Rosenberger et al. Gene expression profiling has shown that most of the macrophage’s transcriptional responses to infection can be mediated through TLR signaling.

Converging Pathways Effects of signaling are cell specific
TIRAP, TRIF, TRAM, MyD88 IRAK for TRAF6 or TBK and IKK for IRF3 Beutler, Nature 2004 Effects of signaling are cell specific NF-B activation is the end result of TLR-signaling

TLR Signaling Pathways
TLR2/TLR TLR2/TLR TLR4 TLR3 TRIF Cell membrane MAL MyD88 MAL MyD88 TRIF TRAM H+ NF-B TLR3 TLR7 TLR8 TLR9 TLRs are predominantly expressed on the cell surface; however, a subset (TLR7, TLR8, TLR9, and in some cases TLR3) are retained in intracellular compartments (endosomal & lysosomal compartments). The cellular location of TLRs combined with their tissue expression patterns appropriately positions them to interact with pathogens that are encountered by the host. TLR responses are initiated by ligand-induced multimerization and receptor clustering (Upon stimulation with their appropriate ligands, TLRs in general form homo or hetero dimers in order to induce an effective signaling cascade) leads to the recruitment of primary adaptor molecules – depending on the TLR involved. The majority of the adaptor proteins identified to date contain a TIR domain. So the TRL-adaptor interactions are mediated by homotypic associations between TIR domains of the receptor and the adaptor. The core TLR signaling pathways use MyD88 as the primary adaptor protein and results and NF-kB and mitogen-activated protein kinase (MAPK) activation and the secretion of a core panel of cytokines. TLR2 (in combination with TLR1 or TLR6) and TLR4 utilize MyD88 (Myeloid differentiation factor 88) and TIRAP/MAL as primary adaptors to activate NF- kB and pro-inflammatory cytokine secretion such as IFNs, IL-1. TNF-alpha, IL-12 . Although most TLRs utilize the MyD88-dependent pathway, a subset of TLR responses remains MyD88 independent. These pathways use a variety of different signaling networks that employ a variety of different adaptors. TLR4 uses TRIF (TIR-domain-containing-adaptor) and the TRIF-related adaptor molecule (TRAM) to activate IRF3 and the IFN pathway (TLR-3 also) TLRs 3, 7, 8, and 9 typically localize to endocytic compartments, where they detect a variety of nucleic acids and activate the IFN pathway. TLR3 utilizes TRIF, but not TRAM, to activate IRF3. TLRs 7, 8, and 9 trigger inflammatory cytokine secretion and the IFN pathway through MyD88. Other than MyD88, the signaling intermediates utilized by TLRs 7, 8, and 9 to activate IFN responses remain undefined but involve IRF-7. = activation of the IFN pathway =secretion of IFN-alpha & beta = SWITCH = more detail about MyD88 dependent and independent signaling pathways IRF3 Inflammatory Cytokines Endosome Interferon Pathway NF-B IRF7 TRIF MyD88

TLR4 MyD88-Dependent Signaling TLR4 MyD88-Independent Signaling
MyD88 Dependent and Independent Pathways: Major Role in Phagocyte Response LBP sCD14 LPS LPS MD-2 TLR4 Cell membrane TLR4 MyD88-Dependent Signaling TLR4 MyD88-Independent Signaling MyD88 MAL IRF-3 P p65 p50 NF-kB p65 p50 NF-kB TLR-4 signaling: TLR4 predominently expressed on immune cells (Macrophage, granulocytes, Dcs) LPS, lipopolysaccharides, are major components of outer membrane of Gram-negative bacteria = production of a variety of proinflammatory cytokines (TNF, IFN-b, NO) TLR4 = the receptor for LPS – 1st discovered homologue of Drosophila Toll Upon bacterial infection, a lipid-binding protein (LBP) – an acute phase protein that circulates in the liver, binds to the lipid A moiety of LPS. Soluble CD14 binds and concentrates LPS present outside the cell. LBP-bound LPS forms a ternary complex with CD14, enabling the transfer of LPS to the TLR4-MD2 complex. MD2 is a secreted glycoprotein that acts as an extracellular adaptor protein that binds LPS and is essential for TLR4 signaling to occur. Upon LPS binding – TLR4 homodimerizes and initiates the ensuing signaling cascade that bifurcate into two signaling pathways : MyD88 (Myeloid differentiation primary-response protein 88) dependent and independent pathways. TLR4 ligand LPS is the most powerfull immunostimulator, which can induce endotoxin shock by itself. This potent immunostimulatory activity may be explained by the fact that TLR4 assembles all the adaptors, thereby exerting potent immune responses. TNF COX2 IL-18 Chemokines Chemokines: Rantes, IP-10 IFN IFN- NF-B NF-B

TLR4 MyD88-Dependent Signaling
LPS LBP sCD14 LPS MD-2 TLR4 MyD88-Dependent Signaling TLR4 Cell membrane (-) TOLLIP MAL MyD88 MEKK3 MKK3 MKK7 JNK p38 IRAK4 IRAK1 UBC13 UBV1A IRAK2 TAB1 TAB2 TAK1 TRAF6 IKK- IKK- IKK- IB Proteasome EARLY = in MyD88 -/- mice, activation of NF-kB and MAPK still occurs but in a delayed manner. In addition, IRF-3 phosphorylation and IFN-beta induction were all unaffected in MyD88 -/- mice, thus suggesting that MyD88 is an adaptor protein involved in the EARLY HOST RESPONSE TO INFECTION. MyD88 is an adaptor protein which contains a C-terminal TIR domain and an N-terminal death domain. Second adaptor-like protein = MAL aka TIRAP (TIR domain containing adaptor protein) is indispensable along with MyD88 in TLR4 signaling. IRAK-4 (IL-1R-associated kinases) – phosphorylates IRAK-1 forming a complex which interacts with TRAF-6 (Tumor Necrosis factor associated factor -6) Autophosphorylation then leads to dissociation of the negative regulator of IRAK-1: Tollip Hyperphosphorylated IRAK1 dissociates from the receptor complex to form a new complex with IRAK2 and TRAF6. TRAF-6 physically interacts with the ubiquitin conjugating enzyme complex Ubc13/Ue1A to catalyze the formation of a unique Lys-63 linked polyubiquitin chain that positively regulates the NF-kB pathway. TRAF6 is activated associates with TAK1 (Transforming growth factor-beta associated kinase) binding protein (TAB2), which in turn activates MAPK kinase TAK1, which is constitutively associated with its adaptor protein kinase TAB1 This leads to the activation of MAPKs such as extracellular signal-regulated kinases (Erks), p38 and c-jun N terminal kinase. In addition, TRAF6 activates IkB-alpha kinase complex (IKK) leading to the phosphorylation and degradation of IkB-alpha – and finally the activation of NF-kB. TLR4 ligand LPS is the most powerfull immunostimulator, which can induce endotoxin shock by itself. This potent immunostimulatory activity may be explained by the fact that TLR4 assembles all the adaptors, thereby exerting potent immune responses. p65 IB p50 NF-B TNF COX2 IL-18 Paz S., Nakhaei P,( 2005)

TLR4 MyD88-Independent Signaling
LBP sCD14 LPS LPS MD-2 TLR4 TLR4 MyD88-Independent Signaling Cell membrane TRAM TRAF6 TRIF IKK- Proteasome IKK- IKK- TBK1 IKK IB p65 IB p50 P IRF-3 P MyD88 independent pathway TRIF and TRIF-related adaptor protein molecular (TRAM) recruit the TBK-1/IKKe heterodimer This complex phosphorylates IRF-3, which dimerizes and translocates to the nucleus leading to the activation of IFN-beta genes. TRIF binds to TRAF-6 via the N-terminal TRAF6-binding domain leading to the activation of the signalosome – followed by the ubiquitination and the degradation of IkB, culminating in the late phase NF-kB activation. Rq: TRAM can also activate IRF-7 which in turn induce de production of IFN-alpha. Late induction NF-B IFN- Paz S., Nakhaei P,( 2005)

Inflammatory Cytokines
LPS dsRNA CpG DNA TLR4 ssRNA Cell membrane TRIF Tyk2 Jak1 TRAM Endosome STAT2 STAT1 ssRNA CpG DNA TBK1 TLR7/8 TLR9 STAT2 STAT1 IRF-9 IKK- MyD88 IRF-3 IKK- IKK- IRAK4 IRAK1 IRF-7 Proteasome TRAF6 IB IFN- IFN- p65 IB p50 NF-B IFN Regulation Inflammatory Cytokines Paz S., Nakhaei P,( 2005)

Negative Regulation of TLR Signaling in Phagocytes
MD-2 ST2 SIGIRR Negative Regulation of TLR Signaling in Phagocytes TLR4 (-) Cell membrane MAL IRAK-M (-) MyD88 Cytoplasmic molecules: IRAK-M (restricted to monocytes and macrophages) SOCS1 (Supressor of cytokine signaling 1) A20 (TNFAIP3) Membrane bound molecules: SIGIRR (single immunoglobulin IL-1R-related molecule) ST2 (-) SOCS1 IRAK4 IRAK1 UBC13 A20 (-) TRAF6 UBV1A IB Proteasome IKK- IKK- IKK- Akira S. et al (2004) The inflammatory cytokines produced as a result of TLR signalling, when released in excess, induce systemic disorders that are associated with a high mortality rate – such as endotoxic shock, which can be induced by the TLR4 ligand LPS. So as TLR signals commit organisms to inflammatory responses, strict regulation of these signals is important for the protection of hosts against excessive inflammation. IRAK-M (restricted to macrophages and monocytes) expression increases following stimulation of TLR ligands - lacks kinase activity. In response to TLR ligands, IRAK-M deficient mice show increased production of inflammatory cytokines and defective induction of LPS tolerance (= transient state of hyporesponsiveness to subsequent stimulation with LPS, which is induced by the administration of TLR ligands in vitro and in vivo). IRAK-M prevents the dissociation of IRAK-1 and IRAK-4 complex from MyD88 – therefore preventing the formation of the IRAK1-TRAF6 complex. SOCS1 : member of the SOCS family of proteins, which are induced by cytokines and negatively regulated cytokine-signaling pathways. SOCS1 expression is induced in macrophages following LPS or CpG stimulation - + SOCS1 deficient mice are found to be hypersensitive to LPS-induced endotoxic shock. Although it was been shown that SOCS1 ass. With IRAK – the precise mechanism remains unclear. A20: has been shown to interact with TRAF6 and IKKgamma. – A20 has critical physiological functions in restricting macrophage responses to systemic LPS and protecting mice from endotoxic shock. In addition to these cytoplasmic molecules, the negative effects of which are induced by TLR signaling, membrane bound molecules that contain TIR domain – such as SIGIRR and ST2. SIGIRR & ST2 negatively regulate of TLR signaling. SIGIRR deficient mice were found to be highly sensitive to LPS-induced endotoxic shock. It’s been shown that SIGIRR also transiently interacts with TLR4, IRAK1 and TRAF6 (in addition with adaptor interaction) . ST2 deficient mice showed increased production of inflammatory cytokines in response to LPS & ST2 overexpression was found to inhibit NF-kB activation. p65 IB p50 TNF COX2 IL-18 NF-B

Phagocyte Sabotage: Evading TLR Signaling
Yersinia LcrV Changing the target: Camouflaging or directly modifying the molecules that trigger TLR signaling (ex: P. aeruginosa). Crossing the wires: Interfering with downstream TLR-mediated signaling or to express TLR agonists (ex: Y. pestis). Sneaking through the back door: Bacteria such as Shigella sp. and Listeria sp. express proteins that facilitate their invasion of macrophages. Pseudomonas LPS TLR2/TLR TLR2/TLR TLR4 (-) Cell membrane MAL MyD88 TRIF TRAM Cytosolic Listeria Changing the target: to avoid detection by macrophages, some bacteria modify their surface by camouflaging or directly modifying the molecules that trigger TLR signaling (ex: many Gram – bacteria alter their LPS structure: Pseudomonas aeruginosa). Crossing the wires: pathogens will allow recognition by TLRs but to interfere with downstream TLR-mediated signaling or to express TLR agonists (ex: LcrV produced by Yersinia pestis) Sneaking through the back door: Bacteria such as Shigella sp. and Listeria sp. express proteins that facilitate their invasion of macrophages and escape from the membrane bound compartment, thereby minimizing the amount of time by which they might activate TLR-based signaling. Rosenberger C.M. et al., (2003) Going to concentrate on macrophages bcs… Macrophages are a common target for bacterial pathogens that benefit from avoiding an encounter with the immune system, as well as those aiming to secure systemic spread. As the central determinants of the course of infection, this well-situated, mobile and expandable cell population provides an early warning system for infection, macrophages have several qualities that allow them to function as both sentinels and the first line of defense against infection. Macrophages form an essential barrier that pathogens must overcome to be successful, and diverse strategies are used by different bacterial pathogens to subvert macrophages. Macrophages lack of specialization (ex: don’t migrate to lymph node like DCs to initiate naïve T cell activation) allow them to function as surrogate killing cells or APCs in the absence or together with, more highly specialized cells. THEREFORE : pathogens cannot avoid adaptive and innate IR if they do not have a strategy for dealing with macrophages. Gram- bacteria can alter their LPS structure to (1) impair recognition and (2) protect themselves from host-derived antimicrobial peptides that can damage the bacterial membrane. P.aeruginosa : causes chronic infections in patients with CF. It alter it’s LPS structure during the diseases. EARLY stages of infection – P.a. expresses LPS that has a penta-acetylated lipid A structure – this triggers the release by macrophages of 100-fold less TNF-alpha and IL-8 when compared with hexa-acetylated LPS – allows initial colonizing of the lungs. LATER stage of infection, the bacteria express a hexa-acetylated LPS that triggers a stronger inflammatory response when recognized by TLR4 on macrophages – thus triggering the lung pathology that is seen in patients at later stages of infection. LcrV: interacts with TLR2 to modify macrophage cytokine production by increasing the secretion of IL-10, which is a cytokine that attenuates the inflammatory response and increases bacterial survivial. Ironically, bacterial interference with TLR2 signaling, makes TLR-based recognition a detriment to the host response to Yersinia, as mice expressing TLR2 are more susceptible to Yersinia infections. Listeria and Shigella : Not to be foiled though, macrophages have recently been shown to have a cytosolic surveillance system that recognizes unidentified Listeria structures – this causes p38 mitogen-activated protein kinase (MAPK) signalling and the subsequent transcription of INF-b and IL-8. Macrophages are able to discriminate between foreign molecules and to assess their cellular location theoretically allows these cells to activate the signaling pathways that are best suited to facilitating the clearance of each type of pathogen in its particular niche. Although it has not yet been reported in macrophages, epithelial cells have a family of proteins, one of which, nucleotide-binding oligomerization domain (NOD1).- this activates the serine-threonine kinase receptor interacting protein -2 rip-2, which, through activation of the inhibitor of NF-kB (ikB) complex (ikK) activates NF-kB-mediated transcription. NF-B Inflammatory Cytokines Nature Reviews Molecular Cell Biology 4; (2003);

Leishmania-Induced Chemokine Expression
LPS TLR4 MyD88 independent MyD88 (-) IRF-3 SHP-1 IRAK-1 TRAF6 ? IKKs IkB-NFkB NF-kB AP-1 Chemokines (MCP-1, MIP-1a/b, MIP-2) No NO No CD14 NO CD14 Chemokines (Rantes, IP-10, MCP-1, MIP-1a/b, MIP-2, Eotaxin) IFN-b

Chemokines, linking innate and adaptive immunity
- inducible CKs are not normally expressed until after injury, infection or other inflammatory stimulus - all innate immune cell, immature and mature DC, not-activated and activated lymphocytes express receptors for inflammatory CKs and thus are able to migrate to and infiltrate the site of inflammation - tissue Mph and DC are the first ones who start inflammatory reaction to injury or pathogen

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