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Macrophage Hematopoietic stem cell (HSC) Myeloid pregenitor Granulocyte-monocyte progenitor monocyte macrophage Bone marrow Blood: 1-6% leukocyte Tissue Macrophage is derived from hematopoietic stem cells in bone marrow. Hematopoiesis: the formation of blood cells

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  • 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

  • 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]