-
MacrophageHematopoietic stem cell(HSC)Myeloid
pregenitorGranulocyte-monocyte progenitormonocytemacrophageBone
marrowBlood: 1-6% leukocyteTissue Macrophage is derived from
hematopoietic stem cells in bone marrow.Hematopoiesis: the
formation of blood cells
-
Destroy bacteria by phagocytosis.MacrophageActivate other immune
function.Phagocytose apoptotic cells
-
MononuclearPhagocytesBlood - monocytes (1-6% WBC)Tissues -
macrophagesmature form of monocytesfound in tissues (ex.,
gastrointestinal tract, lung, liver, brain, skin, spleen);
reticuloendothelial system (RES)Functions: Inflammation- respond to
injury, infection, other foreign substancesPhagocytize and kill
pathogensWound repair, angiogenesisAntigen presentation (activate
adaptive immunity)Tumor surveillance and cytotoxicity
-
Watched the reaction to a splinter inserted into a starfish.
Hemocytes (amoeba-like cells) arrived and tried to ingest the
foreign body; if they could not, they walled it off. Mammals do
exactly the same thing to foreign bodies. Elie Metchnikoff: Father
of Macrophages1908 Nobel prizePhagocytosis- to devour
-
Oyster hemocyteMouse macrophageSimilarity in appearance
invertebrate and mammalian phagocyte striking; also use many of the
same cytotoxic mechanisms (e.g., production ROS)
-
Inflammatory Responses Injury or
-
First Step: Activation of Vascular Endothelial Cells by
MacrophagesEndotheliumForm blood vesselsMacrophages present release
TNFa and IL-1: upregulated expression of adhesion molecules on
endothelium
P-selectinE-selectinICAM-1
Initiate PMN rolling, adherence (LFA-1) Release chemokines
(e.g., IL-8) induce PMN extravagationPMN first to respond (within
hours)Monocyte second wave (24-48 hr)
-
Leukocyte Adhesion, Diapedesis and Emigrationselectins
-
Localization and Destruction of Pathogens and Foreign
SubstancesChemotaxis: migration to injured or infected site;
mediated by chemotactic factors; complement, fMLP, C-X-C (PMN,
IL-8) and C-C (mono, MCP-1) chemokinesPhagocytosis: ingestion of
foreign substances; receptor mediated, active process, requires
energy
-
Localization and Removal of Foreign SubstancesMetabolic
Destruction intracellular digestion, killing
Oxygen independent: defensins and granular cationic proteins,
lactoferrin, lysozyme, acid hydrolases
Oxygen dependent: myeloperoxidase, hydrogen peroxide, superoxide
anion, hydroxyl radicals, nitric oxide, peroxynitrite
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Inflammation is More than a Local Tissue Responses
-
Secretory Functions of MacrophagesBinding proteins (transferrin,
fibronectin)Complement componentsProteolytic enzymes
(lysozyme)Enzyme inhibitors (a2-macroglobulin)Endogenous pyrogen
(IL-1)ROS (superoxide, hydrogen peroxide, hydroxyl radical)RNS
(nitric oxide, peroxynitrite)Bioactive lipids (PAF, PG, LT,
TBX)Chemokines (C-C and C-X-C)Growth factors (FGF, EGF,
CSF)Proinflammatory cytokines (IL-1, TNFa, IL-6)Angiogenic factors:
VEGFMatrix remodeling proteins: TGFb, MMP
-
Stopping Inflammation: Wound Repair and AngiogenesisInflammatory
macrophages release mediators that Down regulate inflammation (eg.,
IL-10)Inhibit inflammatory cell recruitmentBlock specific immune
responsesInitiate wound repair; matrix remodeling (MMPs,
TGFb)Recruit fibroblasts (FGF)Induce angiogenesis (VEGF)
-
What Happens When Inflammation Fails to Resolve?Frustrated
Phagocytosis Foreign Body ResponseMacrophages wall off injurious
agentChronic inflammationGranulomasTissue InjuryCancer
-
Suture materialSilicone dropletsClear globules of silicone
released breast implant cannot be ingested; MP accumulate to wall
off the material; note MP that has become a multi-nucleated giant
cell showing the asteroid bodies characteristic of the foreign body
reaction. Suture material is not digestible by macrophages, so it
has been walled off by fibroblasts.Foreign Body Reactions
-
Macrophage Mediators Can Damage Host Tissueschemokines
-
Reactive Oxygen Species
-
Reactive Nitrogen IntermediatesNitric oxide and
peroxynitriteNitric oxide- formed from l-arginine by the enzyme
nitric oxide synthase (NOS)Macrophages: (NOSII) induced by
inflammatory cytokines (IFNg, TNFa) and bacterially-derived
products (LPS)Highly labile; oxidizes nucleic acids, membranes,
proteinsNitric oxide reacts with superoxide anion forming
peroxynitrite
-
Proinflammatory CytokinesTumor necrosis
factor-aInterleukin-1Interleukin-6Interleukin-18ChemokinesInterferon-g
-
Tumor Necrosis Factor-aProinflammatoryPrimes phagocytes to
produce ROI and RNICytotoxicInduces apoptosis and necrosis
-
Macrophage Processing of AntigensMacrophages function as
accessory cells or antigen processing cells (APC)Macrophage
associated antigen is 1000x more immunogenicProcessing of antigens
involves change so that it binds MHC II (Ia) proteins; may involve
unfolding, partial degradation, selection for epitope with high
affinity for MHC IIRequired for T-helper cell recognition of
antigensOther APC: B cells, epithelial cells, dendritic cells
-
How is it Possible for Macrophages to Perform all of these
Functions?Macrophages functionally polarized into subpopulations by
inflammatory signals in microenvironmentM1 macrophagesActivators:
LPS, IFNg, TNFa, TLR ligandsCytotoxic (pathogens, tumor
cells)/proinflammatory activityRelease ROS, RNS, IL-12, TNFa, M1
chemokinesPromote Th1 responsesM2 macrophages (alternatively
activated) Activators: IL-4, IL-13, IL-10, immune
complexesAntiinflammatory/wound repair activityRelease IL-10, TGFb,
PDGF, VEGF, MMP, EGF, FGFImmunosuppressivePromote Th2 responses
-
M2 MacrophagesM2a-activated by IL-4, IL13
M2b- activated by immune complexes and TLR agonists or IL-1M2c
(tumor associated macrophages)- activated by IL-10, TGFb,
glucocorticoids**active in wound repair, angiogenesis, chronic
inflammation
-
Tumor Associated Macrophages Found within tumor
microenvironmentM2 phenotypeRespond to cytokines (CSF-1) and
chemokines (MCP-1) released by tumor cellsHijacked by tumor cells
to release mediators that contribute to tumor promotion,
progression, angiogenesis and metastasisEGF, VEGF, MMP, IL-1, IL-6,
chemokines
-
Macrophage Phenotypes and Cancer M1 M2Markers: IL12, TNF,
IL6,ROS IL-4, IL-10, TGFBFunctions: Attract lymphocytes Decrease
lymphocyte entry Activate lymphocytes Decrease in lymphocyte
activation Kill tumor cells Increase in angiogenesis Increase tumor
cell growth
-
Macrophages adopt heterogeneous phenotypes according to the
activating stimuli
-
Macrophages may determine the type of T cell and B cell response
to be triggered Macrophages participate in early recognition of
pathogens. Depending on the type of receptors engaged during these
early events, macrophages may produce IL-12 or IL-10
(messengers/cytokines)IL-12 activates a particular type of CD4+ T
cell, known as a Th1 cell (h: helper) and the activation of NK
cells; Th1 cells promote cellular immune responses mediated by
activated macrophages, CD4+ and CD8+ T cells (involved in killing
of intracellular pathogens)IL-10 activates CD4+ Th2 cells that lead
to the production of certain types of antibodies by B cells and the
elimination of extra cellular pathogens
-
Macrophage exhibit immune regulatory functionsMacrophages in
some cases can attenuate (suppress) the activation of T cells,
specially in immune-privileged sites which include the eye, brain,
ovary and testisThese sites need to be protected from overwhelming
inflammationMacrophages can exert immunosuppressive effects by
mechanisms that involve suppressive cytokines present in fluids
from immune-privileged sites such as TGF-IL-10, prostaglandins and
nitric oxide are also potent macrophage-derived inhibitors of T
cell responses
-
How do Macrophages Recognize Pathogens?
-
Phagocytosis of Bacteria by Macrophages
-
How do Macrophages Identify Microbes?Pattern Recognition
Receptors (PPR )Recognize pathogen associated molecular patterns
(PAMP); conserved molecular patterns on microbes Identify a class
of microbes; ex., LPS, LTA, peptidoglycan, lipoarabinomannan,
dsRNA, mannose, b-glycansPAMP are often essential for microbe
survivalAction TimeImmediate activation of effectorsDelays need for
adaptive immunity
-
Macrophage recognizes bacteria by Pattern Recognition Receptors
(PRRs). PRRs recognize Pathogen-Associated Molecular Patterns
(PAMPs).LPS (Gram negative)Lipoteichoic acids (LTA) (Gram
positive)Peptidoglycan (Gram positive)Mannose-containing
carbohydratesFlagellinUnmethylated CpGBacteriaVirus:Double-stranded
RNAFungi: ZymosanParasite:GPI-linked proteins
-
present on microbes, but not on human cells.invariant features
of microbes.essential to microbes.Pathogen Associated Molecular
Patterns (PAMPs)Distinguish foreign vs self.Can be recognized by a
limited number of receptors.Cannot escape recognition by
mutation.
-
Pattern Recognition Receptors (PRR)Three broad classes based on
expression profile, localization, functionPRR that signal an
infection Toll Receptor FamilyExpressed externally or
internallyBinding activates pro-inflammatory signaling
pathwaysPhagocytic (endocytic) PRRExpressed on the surface of
phagocytic cellsMediate uptake of microbe into phagocytesSecreted
PRRSecreted by MP, epithelial cells, hepatocytesActivate
complement, opsonins, function as accessory proteins for PAMP
recognition
-
Toll-like Receptor (TLR) FamilyFirst discovered in
DrosophilaThirteen receptors identified in mice and
humansRecognized motifs (PAMP)-lipopolysaccharide (LPS) from
Gram-negative cell walls-peptidoglycans from the cell walls of both
Gram-negative and Gram-positive bacteria -viral double-stranded RNA
-CpG-rich bacterial DNA
-
Examples of TLR and Ligands
Receptor(Pattern Recognition
Receptors)Ligand(Pathogen-Associated Molecular
Patterns)TLR1Heterodimerizes with TLR2TLR2PGN, some LPS, some LTA,
lipoproteins, AraLAMTLR3dsRNATLR4Gram(-) LPS, Taxol, some LTA,
HSP60TLR5FlagellinTLR6Heterodimerizes with
TLR2TLR7ImidazoquinolineTLR9Bacterial DNA (CpG)
-
Single ligand-single response vs. multiple ligands-complex
response
-
Accessory Proteins for TLR-4Binding requires several accessory
moleculesLBP/MD-2 (Macrophages)RP105 / MD-1 (B
cells)MD-2MD-2MD-2
-
Surface Expressed PRRthat Bind Bacterial
CarbohydratesMannose-binding receptor (C-type lectin)Recognizes
patterns of mannose residues in a certain spatial orientation
unique to microbesOnly found on macrophages (not monocytes or
PMN)Glucan ReceptorPresent on all phagocytes
-
Surface Expressed PRR thatBind other Bacterial
ComponentsScavenger ReceptorsRecognize charged ligandsPolyanionic
ligands (ds-RNA, LPS, LTA)Acetylated low-density lipoproteins
(LDL)Found on all phagocytes (CD36; CD68)MARCO
(macrophage-specific, binds bacterial cell walls and
LPS)Phagocytosis of apoptotic cellsMFG-E8 (released from activated
macrophages and binds to apoptotic cells via
phosphatidylserine)
-
Secreted Pattern Recognition MoleculesAcute Phase
ProteinsImportant in complement activationOpsonization of microbial
cellsPrimarily produced by the liver but can be produced by lung
(SP) or phagocytes
-
Secreted Pattern Recognition MoleculesCollectinsRecognize
microbial carbohydrate (CRD) domainMannan-binding lectinSurfactant
proteins (SP-A / SP-D) (lung)PentraxinRecognize phosphorylcholines
on microbes;Lipid TransferasesRecognizes
peptidoglycansPeptidoglycan recognition proteins (PGRS)LPS binding
protein (LBP
-
INNATE IMMUNITYPHYSICAL BARRIERSSkin, mucous membraneCELLS
granulocytes, monocytes, macrophagesCHEMICAL BARRIERS pH, lipids,
enzymes ADAPTIVE IMMUNITYHUMORAL B cells antibodiesCELL MEDIATED T
cells lymphokinesMP
-
Cellular Interactions in the Immune SystemAGMPPA
BSensitizedBActivatedTh MPTreg SensitizedThTcytBmemplasma Y Antigen
destructionMP(+) (+)(-)(-)(+)(+)(-)Th1Th2
-
Toll-like Receptor SignalingIRAKMD-2MAPKResulting in the
activation of gene transcription
-
Nucleotide-binding oligomerization domain (NOD) proteins
-cytoplasmic surveillance proteins-bind
peptidoglycansIntracellular PRR
-
Intracellular PPRProtein kinase receptor (PKR)Activated upon
binding to dsRNA (viruses)Blocks viral and cellular protein
synthesis (eIF2a)Activates NF-kB, MAP kinase STAT & IRF
signaling pathwaysInduces apoptosis of infected cells and IFNa/b
production2-5 Oligoadenylate Synthase and RNaseL Family of
IFN-inducible enzymesActivated by dsRNA RNaseL degrades viral and
host RNAInduces apoptosis
-
Toll-like Receptor (TLR)Leucine-rich repeats (LRRs)Toll/IL-1
receptor (TIR) domain membrane10 TLRs in humanTLR6/TLR2:
peptidoglycan, GPI, zymosan
TLR4/TLR4: LPS, LTA
TLR5: flagellin
TLR9: unmethylated CpG
TLR3: dsRNA
-
Activation of TLR by PAMP induces the expression Of many genes
involved in immune response.
-
Activation of Toll-like Receptors by PAMP (I)TLR1PAMPInteraction
of TLR with PAMPactivates TLR.TLRPAMPMyD88Activated TLR interacts
with MyD88.
-
Activation of Toll-like Receptors by PAMP (II)TLRPAMPMyD88
(adaptor protein)IRAKMyD88 interacts with IRAK
kinase.TLRPAMPMyD88phosphorylatinAutophosphorylation of IRAK.
-
Activation of Toll-like Receptors by PAMP
(III)TLRPAMPMyD88TRAF6ubiquitinationActivation of TRAF6
inducesAutoubiquitination.TLRPAMPMyD88TRAF6ubiquitinationTAK-1Ubiquitinated
TRAF6 interacts and Activates TAK-1.
-
Activation of Toll-like Receptors by PAMP
(IV)TLRPAMPMyD88TAK-1IKKIKK-PMKKMKK-PTAK-1 phosphorylates IKK and
MKK kinases.Nuclear
envelopecytoplasmnucleusIKK-PMKK-PI-BNF-BNF-BGene
expressionAP-1
-
TLR signaling pathwayPAMPTLRPhosphorylation cascadeActivated
transcrption factor (NF-B, AP-1)Expression of genes involved in
immune responseInflammatory mediatorsAnti-microbial
factorsAntigen-presentation to T cellsActivates other immune
functionsComplementDestroy phagocytosed Bacteria.
-
Activated macrophage secrets inflammatory cytokinesCytokines are
low-molecular weight, secreted signaling proteins.
-
Activated macrophage secretsInterleukin-1 (IL-1)Tumor necrosis
factor-1(TNF-)Interleukin-6 (IL-6)Interleukin-12
(IL-12)Interleukin-8 (IL-8)(chemokines, CXCL8)
-
C5a, C3a, C4a increases local blood flow, vascular permeability,
and extravasation of leukocytes.skinC5aC3aC4aplasmaleukocytesHeat
and redness (erythema, vasodilation)Swelling (edema)Inflammation:
heat, pain, redness, swellingPlasma brings more complement and
antibodiesextravasation
-
IL-1, TNF-a induces inflammation, similar to C5a, C3a, C4a.IL-8
(CXCL8) and C5a acts as chemoattractantsTo recruit Neutrophils to
the site of infection.
-
IL-1, TNF-, and IL-6 have systematic functions 1. Acute phase
responseIL-1, TNF-, IL-6LiverBlood circulationAcute phase
proteinsC-reactive proteinMannose-binding lectinComplement
activationFacilitate phagocytosis
-
IL-1, TNF-, and IL-6 have systematic functions.2. FeverIL-1,
TNF-, IL-6 (endogenous pyrogens)HypothalamusIncrease body
temperatureFat, Muscle (increase energy mobilization)Decrease
bacteria replication
-
Overproduction of TNF-a and IL-1 can cause Septic
shock.Endotoxin (LPS) from Gram-negative bacteria (e.g. E.
coli)Blood circulationMassive macrophage activation in liver and
spleenOverproduction of TNF- and IL-1Dilation of blood vessels and
massive leakage of fluid into tissues throughout the
body.Widespread blood clotting (disseminated intravascular
coagulation).Multiple organ failureSeptic Shock
-
Macrophage (and mast cell) also produces lipid mediators of
inflammationMembrane phospholipidsArachidonic
acidProstaglandinLeukotrieneCycloexygenese pathwayLipoxygenase
pathwayInflammationVasadilation, increased blood vessel
permeability, Neutrophil recruitment
-
Phagocytosis is mediated by phagocytic receptorsand opsonin
receptors.
-
Phagocytic Receptors1. Scavenger Receptors (SRs)Bind to many
microbial ligands (LPS, LTA, etc). 2. Macrophage Mannose Receptor
(MR)Bind to mannose-containing microbial carbohybrates.3. -Glucan
ReceptorBind to glycan in microbial cell walls.
-
Opsonin ReceptorsbacteriaMacrophageComplement receptor (CR: CR1,
CR3, CR4) bacteriaMacrophageImmunoglobulin Fc receptor1. Complement
receptors (CRs)2. Immunoglobulin Fc receptors3. Collectin receptors
Opsonin: C3b or its cleavage products (iC3b)Opsonin:
antibodyOpsonin: collectins (oligomeric C-type lectins) binds to
bacterial carbohydrates.Mannose binding lectin (MBL) binds to
mannose containing carbohybrate.4. Pentraxin receptorsOpsonin:
C-reactive proteins (CRP) binds to phosphocholine in LPS.
-
Phagocytosis (I)Initiated by phagocytic receptors or opsonin
receptors.macrophagePAMP (LPS, peptidoglycan, etc)Opsonin (C3b, Ab,
etc)Phagocytic receptors (Scavenger receptors, etc)Opsonin
receptors (CRs, Ig Fc receptors, etc)macrophage1. Ligand-receptor
interactionPAMP-Phagocytic ReceptorOpsonin-Opsonin Receptors
-
macrophagePhagocytosis (II)pseudopodiaActin polymerization2.
Engagement and clustering of receptorsIntracellular signalsLocal
actin polymerizationPseudopodia formationphagosome3. Phagosome
formation
-
Phagocytosis (III)phagosomelysosomephagolysosome4. Fusion of
phagosome with lysosome to form Phagolysosome.Bacteria is degraded
within the phagolysosome.Macrophage activationOxidaseO2O2.-Nitric
oxide synthetase(NOS)Arginine, O2, NAPDHNOSuperoxide anionNitric
oxideHighly toxic to bacteriaRespiratory burst
-
Phagocytosis (IV)6. Exocytose degraded material5. Present part
of the degraded peptide to T cells.
-
Recognition of Bacteria by MacrophageToll-like Receptors
(TLRs)Phagocytic ReceptorsScavenger Receptors (SRs)Macrophage
mannose receptor (MR)-Glucan receptorsOpsonin ReceptorsComplement
Receptors (CRs)Immunoglobulin Fc ReceptorsCollectin
ReceptorsPentraxin Receptors
-
LPS (Gram negative)Lipoteichoic acids (LTA) (Gram
positive)Peptidoglycan (Gram positive)Mannose-containing
carbohydratesFlagellinUnmethylated CpGBacteriaPathogen Associated
Molecular Patterns (PAMPs)
-
BacteriaMacrophagephagocytosiscytokinesInfammationOther immune
functionT cell activationAcute phaseResponseLipid mediator
-
BacteriaComplementlysisinflammationMacrophageOther immune
functionsphagocytosisAcute phase reactionOpsonizationC-reactive
proteinMBLNeutrophilsT cell activationMast cell
-
Damage to blood vessel also induces inflammationBlood vessel
damageActivation of Hageman factorKinin systemBlood clotting
systemProteolytic cascadeBradykininFibrin degradation
productInflammationVasodilatin, increased vascular permeability,
Pain
Classical activation of macrophages (M1) by interferon- (IFN)
creates a cell that actively secretes inflammatory cytokines and
chemokines, phagocytoses and kills invading microorganisms, and
initiates adaptive immune responses.16,17 In contrast, macrophages
stimulated by interleukin (IL)-4/IL-13 (M2) display a distinct
alternative pattern of activation.1821 M2 cells play a role in
directing Th2 humoral responses, allergic and parasitic responses
and the coordination of repair following an inflammatory reaction.
These functional differences are reflected in the expression levels
of surface proteins, the inflammatory cytokine production profile
and the expression of the two opposing effector molecules,
inducible nitric oxide synthase (iNOS) and arginase.
Hallmarks of an Inflammatory ResponseRednessHeat
SwellingPain
IL-1, IL-6, and TNF-a activate hepatocytes to synthesize
acute-phase proteins, and bone marrow endothelium to release
neutrophils. The acute-phase proteins act as opsonins, while the
disposal of opsonized pathogens is augmented by enhanced
recruitment of neutrophils from the bone marrow. IL-1, IL-6, and
TNF-a are also endogenous pyrogens, raising body temperature, which
is believed to help eliminate infections. A major effect of these
cytokines is to act on the hypothalamus, altering the bodys
temperature regulation, and on muscle and fat cells, altering
energy mobilization to increase the body temperature. At elevated
temperatures, bacterial and viral replication are decreased, while
the adaptive immune response operates more efficiently.
LPS from Gram negativeLTA lipotechoic acid from Gram
positivePeptidogkycansLipoarabinomannan - from microbacteria)dsRNA
-produced by most virusesMannans from fungiB-glucans from fungi
These signaling pathways are evolutionarily conserved.
Type 1 transmembrane receptorCalled TIR because it is homologous
to the intracellular domain of IL-1 receptor.-This is a conserved
signaling molecule found in a number of cytosolicproteins usually
involved in host defense.Most TLRs recognize microbial products as
single chains, however some like TLR4 form dimers as use accessory
proteins and some form heterodimers.LPB (a serum protein) binds to
LPS and transfers it to CD14. CD14 can exist on the cell surface
(MQ, DC) or soluble. It does not have a tranmembrane portion but
has been shown to be important in LPS recognition
(CD14-/-mice).
MD-2 does not have a transmembrane domain and is also required
for LPS recognition.What directly contacts LPS is not known but
some studies indicate that MD-2 and TLR4 do.
RP105 is on B cells and has a ectodomain similar to TLR4. It
associates with MD-1 (homologue of MD-2). However, it lacks a TIR
domain. In its place there is a cytoplasmic tail with a tyrosine
phosphorylation motif. Cross-linking of this receptor causes B cell
activation (proliferation, CD80/CD86 expression, Src-family
tyrosine kineases). Delection of the gene causes reduced B cell
responsiveness to LPS but this is not complete.lipoteichoic acid =
LTA
Acute-phase proteins are produced by liver cells in response to
cytokines released by macrophages in the presence of bacteria. They
include serum amyloid protein (SAP) (in mice but not humans),
C-reactive protein (CRP), fibrinogen, and mannan- binding lectin
(MBL). SAP and CRP are homologous in structure; both are
pentraxins, forming five-membered discs, as shown for SAP
(photograph on the right). CRP binds phosphorylcholine on certain
bacterial and fungal surfaces but does not recognize it in the form
in which it is found in host cell membranes. It both acts as an
opsonin in its own right and activates the classical complement
pathway by binding C1q to augment opsonization. MBL is a member of
the collectin family, which includes C1q, which it resembles in its
structure. We have already seen how MBL activates complement (see
Section 2-7) and how it binds to pathogen surfaces (see Fig. 2.28).
Like CRP, MBL can act as an opsonin in its own right, in addition
to activating complement. SP-A and SP-D are surfactants A and D,
both of which are collectins that coat bacterial surfaces,
facilitating their phagocytosis. Photograph courtesy of J. Emsley.
Photo from Nature 1994, 367:338-345. 1994 Macmillan Magazines
Limited. Collectin: a family of structurally related,
calcium-dependent sugar-binding proteins or lectins containing
collagen-like sequences.
All mammalian TLRs can signal via MyD88.This is the same pathway
that occurs for IL-1R signaling
TIR (Toll/IL-1 receptor domain)MyD88 (adaptor protein)-has two
domains TIR and DD that form the link between TLR and IRAKIRAK
(IL-1 receptor associated kinase)a serine/threonine receptor
kinaseTRAF6 (TNF receptor associated factor 6)a ubiquitin ligase
(enzyme that links together two molecules)Activate the
transcription factors, NFkB and MAPK (JNK, p38)(nuclear factor kB
and mitogen activated kinase)
Mammalian surveillance mechanism that senses and responds to
bacteria in the cytosal.
LRD region contains a leucine rich repeat.The centrally located
domain is necessary for oligomerization.Effector-binding domain is
a CARD domain in mammals.
Activates transcriptional pathways that are antimicrobial
In plants the resistance genes interact with pathogens and
induce the equivalent of an inflammatory response.
Nucleotide binding domain NBDLeucine rich repeat LLRCaspase
activation and recruitment domain - CARD
Inohara N, Nunez G. NODs: intracellular proteins involved in
inflammation and apoptosis. Nat Rev Immunol. 2003 May;3(5):371-82.
Review. PMID: 12766759 [PubMed - indexed for MEDLINE]