Regulation of TLR by endogenous ligand (Homo sapiens)

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7, 10, 33, 385, 16, 316, 12, 2322, 273, 9, 25, 288, 19, 30, 36111118, 2911, 15, 20135, 16, 319, 24, 25, 37cytosolnucleoplasmcytosolendosome lumen10xdHF-10xglutamyl semialdehyde (Pro)-6xL-tyrosine residue-3xOxoH-2xmodified L-lysine residue-N'-formyl-L-kynurenine-APOB(28-4563) MyD88-independentTLR4 cascade HC23,45-HMGB1 TLR4:TLR62xN4GlycoAsn-LY96 CD14(20-345) TLR4:LY96:S100A8:S100A9PL SFTPA oligomer 7-ketocholesterol S100A1 2xN4GlycoAsn-TLR4 Lipoteichoic acidTLR1 TLR4:TLR6:CD36:oxLDLHC23,45-HMGB1CHEST 2xN4GlycoAsn-TLR4 hydroxy fatty acid HC23,45-HMGB1 TAGs oxidized phospholipids 10xdHF-10xglutamyl semialdehyde (Pro)-6xL-tyrosine residue-3xOxoH-2xmodified L-lysine residue-N'-formyl-L-kynurenine-APOB(28-4563) hydroxy fatty acid 2xN4GlycoAsn-TLR4 oxidizedphospholipidshydroperoxy fatty acid CHOL S100A8 2xN4GlycoAsn-LY96 HMGB1TLR1:TLR2PL 2xN4GlycoAsn-LY96 FGA(20-35) SFTPD oligomer oxLDL:CD36TLR4:LY96:cleavedfibrinogenS100A1 2xN4GlycoAsn-TLR4 SFTPD oligomer TLR6 S100A9 SFTPA oligomer Lipoteichoic acid LPSCHOL TAGs TLR2 FGB(31-44) TLR4:LY96CD14(20-345)2xN4GlycoAsn-TLR4 2xN4GlycoAsn-LY96 FGG 2xN4GlycoAsn-TLR4 SFTPA oligomer oxidized phospholipids FGA, FGB, FGGS100A1 dimer:Ca(2+)TLR2 LBPSP-A/SP-D:TLR4:MD2HC23,45-HMGB1:LPSFGG 2xN4GlycoAsn-TLR4 LBP:oxPLS100A8:S100A9hydroperoxy fatty acid 2xN4GlycoAsn-TLR4 FGB(31-44) TLR1 HC23,45-HMGB1:TLR4:LY96Ca2+ lysoPC CHEST LPS MyD88:Mal cascadeinitiated on plasmamembraneFGA(20-35) S100A1:TLR4:LY96lysoPC SFTPD oligomer CD14:oxPLSFTPA/SFTPD:TLR2:TLR12xN4GlycoAsn-LY96 S100A8 TLR6 HC23,45-HMGB1 Ca2+ S100A9 4xPalmC-CD36 2xN4GlycoAsn-LY96 LBP 7-ketocholesterol HC23,45-HMGB1:LTA4xPalmC-CD36 SFTPA oligomer,SFTPD oligomer27322, 32373932342, 3221532402, 322, 3252, 321, 20323539213232, 3240273264, 17322614, 223225


Description

Diverse molecules of host-cell origin may serve as endogenous ligands of Toll-like receptors (TLRs) (Erridge C 2010; Piccinini AM & Midwood KS 2010). These molecules are known as damage-associated molecular patterns (DAMPs). DAMPs are immunologically silent in healthy tissues but become active upon tissue damage during both infectious and sterile insult. DAMPs are released from necrotic cells or secreted from activated cells in response to tissue damage to mediate tissue repair by promoting inflammatory responses. However, DAMPs have also been implicated in the pathogenesis of many inflammatory and autoimmune diseases, including rheumatoid arthritis (RA), cancer, and atherosclerosis. The mechanism underlying the switch from DAMPs that initiate controlled tissue repair, to those that mediate chronic, uncontrolled inflammation is still unclear. Recent evidence suggests that an abnormal increase in protein citrullination is involved in disease pathophysiology (Anzilotti C et al. 2010; Sanchez-Pernaute O et al. 2013; Sokolove J et al. 2011; Sharma P et al. 2012). Citrullination is a post-translational modification event mediated by peptidyl-arginine deaminase enzymes which catalyze the deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 5686938
Reactome-version 
Reactome version: 65
Reactome Author 
Reactome Author: Shamovsky, Veronica

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114668view16:13, 25 January 2021ReactomeTeamReactome version 75
113115view11:17, 2 November 2020ReactomeTeamReactome version 74
112349view15:27, 9 October 2020ReactomeTeamReactome version 73
101250view11:14, 1 November 2018ReactomeTeamreactome version 66
100789view20:42, 31 October 2018ReactomeTeamreactome version 65
100331view19:18, 31 October 2018ReactomeTeamreactome version 64
99876view16:02, 31 October 2018ReactomeTeamreactome version 63
99433view14:36, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93389view11:22, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
10xdHF-10xglutamyl semialdehyde (Pro)-6xL-tyrosine residue-3xOxoH-2xmodified L-lysine residue-N'-formyl-L-kynurenine-APOB(28-4563) ProteinP04114 (Uniprot-TrEMBL)
2xN4GlycoAsn-LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
2xN4GlycoAsn-TLR4 ProteinO00206 (Uniprot-TrEMBL)
4xPalmC-CD36 ProteinP16671 (Uniprot-TrEMBL)
7-ketocholesterol MetaboliteCHEBI:64294 (ChEBI)
CD14(20-345) ProteinP08571 (Uniprot-TrEMBL)
CD14(20-345)ProteinP08571 (Uniprot-TrEMBL)
CD14:oxPLComplexR-HSA-8869691 (Reactome)
CHEST MetaboliteCHEBI:17002 (ChEBI)
CHOL MetaboliteCHEBI:16113 (ChEBI)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
FGA(20-35) ProteinP02671 (Uniprot-TrEMBL)
FGA, FGB, FGGComplexR-HSA-8870680 (Reactome)
FGB(31-44) ProteinP02675 (Uniprot-TrEMBL)
FGG ProteinP02679 (Uniprot-TrEMBL)
HC23,45-HMGB1 ProteinP09429 (Uniprot-TrEMBL)
HC23,45-HMGB1:LPSComplexR-HSA-6801229 (Reactome) Analysis of LPS binding to HMGB1 was conducted using a surface plasmon resonance analyses (BIAcore) and ELISA test with LPS-immobilized microtiter wells (Youn JH et al. 2008). Pull-down assays using streptavidin agarose beads and ELISA assay were conducted to map regions within the A and B box domains of HMGB1 that bind to the polysaccharide and lipid A moieties of LPS respectively (Youn JH et al. 2011).
HC23,45-HMGB1:LTAComplexR-HSA-6801223 (Reactome)
HC23,45-HMGB1:TLR4:LY96ComplexR-HSA-5432869 (Reactome)
HC23,45-HMGB1ProteinP09429 (Uniprot-TrEMBL)
HMGB1ProteinP09429 (Uniprot-TrEMBL)
LBP ProteinP18428 (Uniprot-TrEMBL)
LBP:oxPLComplexR-HSA-8869676 (Reactome)
LBPProteinP18428 (Uniprot-TrEMBL)
LPS MetaboliteCHEBI:16412 (ChEBI)
LPSMetaboliteCHEBI:16412 (ChEBI)
Lipoteichoic acid MetaboliteCHEBI:28640 (ChEBI)
Lipoteichoic acidMetaboliteCHEBI:28640 (ChEBI)
MyD88-independent TLR4 cascade PathwayR-HSA-166166 (Reactome) MyD88-independent signaling pathway is shared by TLR3 and TLR4 cascades. TIR-domain-containing adapter-inducing interferon-beta (TRIF or TICAM1) is a key adapter molecule in transducing signals from TLR3 and TLR4 in a MyD88-independent manner (Yamamoto M et al. 2003a). TRIF is recruited to ligand-stimulated TLR3 or 4 complex via its TIR domain. TLR3 directly binds TRIF (Oshiumi H et al 2003). In contrast, TLR4-mediated signaling pathway requires two adapter molecules, TRAM (TRIF-related adapter molecule or TICAM2) and TRIF. TRAM(TICAM2) is thought to bridge between the activated TLR4 complex and TRIF (Yamamoto M et al. 2003b, Tanimura N et al. 2008, Kagan LC et al. 2008).

TRIF recruitment to TLR complex stimulates distinct pathways leading to production of type 1 interferons (IFNs), pro-inflammatory cytokines and induction of programmed cell death.

MyD88:Mal cascade

initiated on plasma

membrane
PathwayR-HSA-166058 (Reactome) The first known downstream component of TLR4 and TLR2 signaling is the adaptor MyD88. Another adapter MyD88-adaptor-like (Mal; also known as TIR-domain-containing adaptor protein or TIRAP) has also been described for TLR4 and TLR2 signaling. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR, whereas Mal lacks the DD. The TIR homotypic interactions bring adapters into contact with the activated TLRs, whereas the DD modules recruit serine/threonine kinases such as interleukin-1-receptor-associated kinase (IRAK). Recruitment of these protein kinases is accompanied by phosphorylation, which in turn results in the interaction of IRAKs with TNF-receptor-associated factor 6 (TRAF6). The oligomerization of TRAF6 activates TAK1, a member of the MAP3-kinase family, and this leads to the activation of the IkB kinases. These kinases, in turn, phosphorylate IkB, leading to its proteolytic degradation and the translocation of NF-kB to the nucleus. Concomitantly, members of the activator protein-1 (AP-1) transcription factor family, Jun and Fos, are activated, and both AP-1 transcription factors and NF-kB are required for cytokine production, which in turn produces downstream inflammatory effects.
PL MetaboliteCHEBI:16247 (ChEBI)
S100A1 ProteinP23297 (Uniprot-TrEMBL)
S100A1 dimer:Ca(2+)ComplexR-HSA-6805958 (Reactome)
S100A1:TLR4:LY96ComplexR-HSA-6805997 (Reactome)
S100A8 ProteinP05109 (Uniprot-TrEMBL)
S100A8:S100A9ComplexR-HSA-5432834 (Reactome)
S100A9 ProteinP06702 (Uniprot-TrEMBL)
SFTPA oligomer R-HSA-391092 (Reactome)
SFTPA oligomer, SFTPD oligomerComplexR-HSA-391108 (Reactome)
SFTPA/SFTPD:TLR2:TLR1ComplexR-HSA-5432872 (Reactome)
SFTPD oligomer R-HSA-391097 (Reactome)
SP-A/SP-D:TLR4:MD2ComplexR-HSA-5432881 (Reactome)
TAGs MetaboliteCHEBI:17855 (ChEBI)
TLR1 ProteinQ15399 (Uniprot-TrEMBL)
TLR1:TLR2ComplexR-HSA-168946 (Reactome)
TLR2 ProteinO60603 (Uniprot-TrEMBL)
TLR4:LY96:S100A8:S100A9ComplexR-HSA-5432865 (Reactome)
TLR4:LY96:cleaved fibrinogenComplexR-HSA-8870679 (Reactome)
TLR4:LY96ComplexR-HSA-166050 (Reactome)
TLR4:TLR6:CD36:oxLDLComplexR-HSA-8869674 (Reactome)
TLR4:TLR6ComplexR-HSA-8869699 (Reactome)
TLR6 ProteinQ9Y2C9 (Uniprot-TrEMBL)
hydroperoxy fatty acid MetaboliteCHEBI:64009 (ChEBI)
hydroxy fatty acid MetaboliteCHEBI:24654 (ChEBI)
lysoPC MetaboliteCHEBI:60479 (ChEBI)
oxLDL:CD36ComplexR-HSA-8869680 (Reactome)
oxidized phospholipidsMetaboliteCHEBI:60156 (ChEBI)
oxidized phospholipids MetaboliteCHEBI:60156 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
CD14(20-345)R-HSA-8869694 (Reactome)
CD14:oxPLArrowR-HSA-8869694 (Reactome)
FGA, FGB, FGGR-HSA-8870678 (Reactome)
HC23,45-HMGB1:LPSArrowR-HSA-6804100 (Reactome)
HC23,45-HMGB1:LTAArrowR-HSA-6804099 (Reactome)
HC23,45-HMGB1:TLR4:LY96ArrowR-HSA-5432825 (Reactome)
HC23,45-HMGB1ArrowR-HSA-6805981 (Reactome)
HC23,45-HMGB1R-HSA-5432825 (Reactome)
HC23,45-HMGB1R-HSA-6804099 (Reactome)
HC23,45-HMGB1R-HSA-6804100 (Reactome)
HMGB1R-HSA-6805981 (Reactome)
LBP:oxPLArrowR-HSA-8869683 (Reactome)
LBPR-HSA-8869683 (Reactome)
LPSR-HSA-6804100 (Reactome)
Lipoteichoic acidR-HSA-6804099 (Reactome)
R-HSA-5432814 (Reactome) The lung surfactant proteins SP-A (also known as SFTPA) and SP-D (SFTPD) have been implicated in the regulation of pulmonary host defense and inflammation. SP-A and SP-D were found to bind to the recombinant soluble form of extracellular TLR2 domain (TLR2) via its C-terminal carbohydrate recognition domain (CRD) in a Ca(2+)-dependent manner (Murakami S et al. 2002; Ohya M et al. 2006). SP-A downregulated TLR2-mediated signaling and tumor necrosis factor alpha (TNFalpha) secretion in TLR2-transfected human embryonic kidney 293 (HEK293) cells upon stimulation with TLR2 ligands such as fungal cell surface component zymosan or bacterial peptidoglycan (PGN) (Murakami S et al. 2002; Sato M et al. 2003). Similarly, SP-A significantly reduced PGN-elicited TNFalpha secretion by human leukemic monocyte lymphoma U937 cell line and rat alveolar macrophages (Murakami S et al. 2002). In primary human monocyte-derived macrophage SP-A regulated TLR2 and TLR4 activity by diminishing proinflammatory cytokine production as the result of a decreased phosphorylation of a key regulator of NFkB, IkBalpha. Nuclear translocation of NFkB-p65 (RELA) was also inhibited (Henning LN et al. 2008). SP-A downregulated kinases upstream of IkBalpha by decreasing the phosphorylation of Akt and MAPKs in response to either LPS (TLR4 ligand) or Pam3Cys (TLR2 ligand) (Henning LN et al. 2008). In addition, SP-A upregulated surface protein expression of TLR2 on macrophages, while it did not affect TLR4 surface expression. The increased TLR2 expression is thought to enhance pathogen recognition by TLR2, while SP-A mediated inhibition of TLR signaling may protect from an overreactive inflammatory response (Henning LN et al. 2008).
R-HSA-5432825 (Reactome) High mobility group box protein 1 (HMGB1) is an endogenous molecule that upon stress can be released into the extracellular milieu (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Bell CW et al. 2006; Beyer C et al. 2012; Yang H et al. 2013).

Using surface plasmon resonance (SPR) analysis recombinant HMGB1 was shown to bind TLR4:LY96(MD2) in a concentration-dependent manner (Yang H et al. 2010; Yang H et al. 2015). The binding required cysteine at the position 106 whereas the C106A HMGB1 mutant failed to bind TLR4:LY96 (Yang H et al. 2010). In addition, C106A and C106S HMGB1 failed to stimulate TNF release in mouse peritoneal macrophages (Yang H et al. 2010). The activity of HMGB1 was found to depend on the redox state of three cysteines at positions 23, 45 and 106 (C23, C45 and C106) (Urbonaviciute V et al. 2009; Venereau E et al. 2012, 2013; Yang H et al. 2012, 2013). Tandem mass spectrometric analysis revealed that the inflammatory activities of HMGB1 required both the formation of an intramolecular disulfide bond between C23 and C45 and the reduced state of C106 (thiol state, C106-SH) (Yang H et al. 2012; Venereau E et al. 2012). Both terminal oxidation of these cysteines to sulfonates (CySO3-) with reactive oxygen species (ROS) and their complete reduction to thiols (CySH) abrogated the cytokine-stimulating activity of HMGB1 in cultured human primary macrophages and mouse macrophage-like RAW 264.7 cells (Yang H et al. 2012; Venereau E et al. 2012). Biosensor-based SPR analysis confirmed that only the disulfide bond (C23-S-S-C45)-containing HMGB1 binds to LY96 (MD2) with high affinity (apparent Kd = 12 nM) regardless of whether LY96 or HMGB1 was immobilized on the sensor chip (Yang H et al. 2015). Moreover, TLR4 and LY96 (MD2) were recruited into CD14-containing lipid rafts of mouse RAW264.7 macrophages after stimulation with HMGB1, suggesting that an optimal HMGB1-dependent TLR4 activation in vitro required the co-receptor CD14 (Kim S et al. 2013). In addition to stimulating cells by direct interaction with innate immune receptors, HMGB1 was found to form immunostimulatory complexes with cytokines and other endogenous and exogenous ligands such as bacterial lipopolysaccharide (LPS) (Youn JH et al. 2008; Wahamaa H et al. 2011; Hreggvidsdottir HS et al. 2009) HMGB1 in complex with LPS, IL1alpha or IL1beta boosted proinflammatory cytokine- and matrix metalloproteinase (MMP3) production in synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients (Wahamaa H et al. 2011; He ZW et al. 2013). HMGB1 was reported to associate and amplify the activity of LPS (TLR4 ligand), CpG-ODN (TLR9 ligand) or Pam3CSK4 (TLR1:TLR2 ligand) in a synergistic manner when added to the cultures of human peripheral blood mononuclear cell (PBMC) (Hreggvidsdottir HS et al. 2009).

R-HSA-5432849 (Reactome) S100A8 (also known as MRP8) and S100A9 (MRP14) are Ca(2+)-binding proteins that are associated with acute and chronic inflammation and cancer (Ehrchen JM et al. 2009; De Jong HK et al. 2015). S100A8 & S100A9 have been identified as important damage-associated molecular patterns (DAMPs) recognized by TLR4 (Foell D et al. 2007; Vogl t et al. 2007; 2012; Kang JH et al. 2015). Surface plasmon resonance studies showed that S100A8 can directly interact with TLR4:MD2 complex with Kd of 1.1-2.5 x 10e-8 M ((Vogl T et al. 2007). Human embryonic kidney cells stably transfected with TLR4,CD14 and MD2 demonstrated a strong induction of proinflammatory cytokines like TNFalpha and IL8 after stimulation with LPS as well as with S100A8 (Vogl T et al. 2007). Induction of NFkB responses by S100A9 in human monocytic THP-1 cell line and mouse bone marrow-derived dendritic cells was TLR4-dependent (Riva M et al. 2012). Moreover, induction of MUC5AC mRNA and protein in normal human bronchial epithelial cells as well as NCI-H292 lung carcinoma cells occurred in a dose-dependent manner trough TLR4 signaling pathway (Kang JH et al. 2015). In addition, S100A8:S100A9 was reported to regulate cell survival of human neutrophils through a signaling mechanism involving an activation of MEK:ERK1 via TLR4 (Atallah M et al. 2012). In experimental mouse models the proinflammatory and TLR4-dependent activities of S100A8:S100AA9 were further confirmed (Vogl t et al. 2007; Loser K et al. 2010; Kuipers MT et al. 2013; Deguchi A et al. 2015).

S100A8 & S100A9 are constitutively expressed in neutrophils, myeloid-derived dendritic cells, platelets, osteoclasts and hypertrophic chondrocytes (Hessian PA et al. 1993; Kumar A et al. 2003; Healy AM et al. 2006; Schelbergen RF et al 2012). In contrast, these molecules are induced under inflammatory stimuli in monocytes/macrophages, microvascular endothelial cells, keratinocytes and fibroblasts (Hessian PA et al. 1993; Eckert RL et al. 2004; Viemann D et al. 2005; McCormick MM et al. 2005; Hsu K et al. 2005). S100A8 & S100A9 tend to form homodimers and heterodimers (Kumar RK et al. 2001; Riva M et al. 2013; Korndorfer IP et al. 2007). The heterodimeric S100A8:S100A9 complex is termed calprotectin and is considered as the predominantly occurring form. In response to stress S100A8:S100A9 is primarily released from activated or necrotic neutrophils to extracellular milieu where it functions as an innate immune mediator of infection, autoimmunity, and cancer (Ehrchen JM et al. 2009; Rammes A et al. 1997; Frosch M et al. 2000; Loser K et al. 2010).

S100A8 and S100A9 protein levels were elevated in patients with a wide range of inflammatory diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, acute lung inflammation, sepsis and vasculitis (Ehrchen JM et al. 2009; van Zoelen MA et al. 2009; Vogl T et a;. 2012; Holzinger D et al. 2012; Rahman MT et al. 2014; Anink J et al. 2015. Increased S100A8 and S100A9 serum levels have been also identified as independent risk predictors for various cardiovascular diseases such as acute coronary syndrome and myocardial infarction (Yonekawa K et al. 2011; Cotoi OS et al. 2014; Larsen SB et al. 2015).

R-HSA-5432852 (Reactome) The hydrophilic pulmonary surfactant proteins SP-A (SFTPA) and SP-D (SFTPD) belong to the C-type lectin family. Members of the C-type lectin family contain an N-terminal collagen-like domain and a C-terminal carbohydrate recognition domain (CRD) (Kishore U et al. 2006). The CRD allows binding to various components, including carbohydrates, phospholipids or charge patterns found on microbes, allergens and dying cells, while the collagen region can interact with receptor molecules present on immune cells in order to initiate clearance mechanisms (Kishore U et al. 2006). SP-A and SP-D are known to bind to a range of microbial pathogens that invade the lungs (Eggleton P & Reid KB 1999; Crouch E & Wright JR 2001; McCormack FX1 & Whitsett JA 2002; Nayak A et al. 2012; Jakel A et al. 2013). SP-A and SP-D form large oligomeric structures to orchestrate the pulmonary innate immune defense by mechanisms that may involve binding and agglutinating pathogens (Kuan SF et al 1992; Griese M & Starosta V 2005; Yamada C et al. 2006; Kishore U et al. 2006; Zhang L et al. 2001). The direct interaction of SP-A with macrophages was shown to promote phagocytosis of Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa (Van Iwaarden JF et al. 1994; Hickman-Davis JM et al. 2002; Ding J et al. 2004; Mikerov AN et al. 2008; Gil M et al. 2009).

SP-A and SP-D were found to bind to the recombinant soluble form of extracellular TLR4 domain (sTLR4) and MD2 in a Ca2+ -dependent manner, with involvement of the CRD region (Yamada et al. 2006; Yamazoe M et al. 2008). SP-A was also shown to interact with CD14 (Sano H. et al. 1999). Studies involving gene knock-out mice, murine models of lung hypersensitivity and infection together with functional characterization of cell surface receptors revealed both pro- and anti-inflammatory functions of SP-A and SP-D in the control of lung inflammation in mammals (Guillot L et al. 2002; Madan T et al. 2001, 2005, 2010; Wang JY & Reid KB 2007; Yamada et al. 2006; Yamazoe M et al. 2008; Wang G et al. 2010). Anti-inflammatory effects of SP-A caused inhibition of NF-kB activation and accumulation of inhibitory protein I kappa B-alpha (IkB-alpha) in LPS-challenged alveolar macrophages (AM) (Wu Y et al. 2004). SP-A also inhibited tumor necrosis factor-alpha (TNFalpha) expression induced by smooth LPS but not by rough LPS in the human macrophage-like cell line U937 cells (Sano H. et al. 1999). In addition, SP-A attenuated cell surface binding of smooth LPS and subsequent NF-kB activation in TLR4/MD2 expressing human embryonic kidney (HEK293) cells (Yamada et al. 2006). Like SP-A, SP-D bound to complex of sTLR4:MD2 was found to down regulate a secretion of TNFalpha and activation of NF-kB in LPS-stimulated AM and TLR4/MD-2-transfected HEK293 cells (Yamazoe M et al. 2008). SP-A and SP-D are thought to prevent LPS-elicited inflammatory responses by altering LPS binding to its receptors, TLR4:MD2 or CD14 (Sano H. et al. 1999; Yamada et al. 2006; Yamazoe M et al. 2008).

R-HSA-6804099 (Reactome) Lipoteichoic acid (LTA) is a component of the cell wall of Gram-positive bacteria. LTA induces a toll-like receptor 2 (TLR2)-mediated inflammatory response upon initial binding to coreceptors CD36 and CD14 (Nilsen NJ et al. 2008).

High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein that under normal conditions binds and bends DNA and facilitates gene transcription. In response to infection or injury, HMGB1 is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Beyer C et al. 2012; Yang H et al. 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013). HMGB1 has been implicated in TLR2-mediated inflammation (Yu M et al. 2006; Park JS et al. 2006). Addition of HMGB1 induced cellular activation and TLR2- and TLR4-mediated NFkappaB-dependent transcription in TLR2- or TLR4-transfected human embryonic kidney-293 (HEK293) cells (Park JS et al. 2006). Mouse Tlr2 was found to associate with immunoprecipitated Hmgb1 from mouse macrophage-like RAW264.7 cell lysates (Park JS et al. 2006). Anti-TLR2 antibodies dose-dependently attenuated HMGB1-induced IL-8 release in TLR2-expressing HEK293 cells and markedly reduced HMGB1 cell surface binding on murine macrophage-like RAW 264.7 cells (Yu M et al. 2006). Moreover, results of ELISA, surface plasmon resonance and native PAGE electrophoretic mobility shift analyses indicated that HMGB1 binds LTA in a concentration-dependent manner and that this binding is inhibited by LBP (Kwak MS et al. 2015). Native PAGE, fluorescence-based transfer and confocal imaging analyses indicated that HMGB1 catalytically disaggregated LTA transfering LTA to CD14. NFkappaB p65 nuclear transmigration, degradation of IkBalpha and reporter assay results demonstrated that NFkappaB activity in HEK293-hTLR2/6 cells was significantly upregulated by a mixture of LTA and soluble CD14 in the presence of HMGB1 (Kwak MS et al. 2015). Furthermore, the production of TNFalpha and IL6 in murine J774A.1 and RAW264.7 cells increased significantly following treatment with a mixture of LTA and HMGB1 compared with treatment with LTA or HMGB1 alone (Kwak MS et al. 2015). Thus, HMGB1 was proposed to play an important role in LTA-mediated inflammation by binding to LTA and transferring LTA to CD14, which is subsequently transferred to TLR2:TLR6 to induce an inflammatory response.

R-HSA-6804100 (Reactome) High mobility group box 1 (HMGB1) is an ubiquitous nuclear protein that is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells in response to infection or injury (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Beyer C et al. 2012; Yang H et al. 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013).

HMGB1 can form immunostimulatory complexes with cytokines and other endogenous and exogenous ligands such as bacterial lipopolysaccharide (LPS) to potentiate proinflammatory response (Youn JH et al. 2008, 2011; Wähämaa H et al. 2011; Hreggvidsdottir HS et al. 2009). The activity of HMGB1 depended on the redox state of three cysteines at positions 23, 45 and 106 (C23, C45 and C106) (Urbonaviciute V et al. 2009; Venereau E et al. 2012, 2013; Yang H et al. 2012, 2013). Tandem mass spectrometric analysis revealed that the inflammatory activities of HMGB1 required both the formation of an intramolecular disulfide bond between C23 and C45 and the reduced state of C106 (thiol state, C106-SH) (Yang H et al. 2012; Venereau E et al. 2012). Both terminal oxidation of these cysteines to sulfonates (CySO3–) with reactive oxygen species (ROS) and their complete reduction to thiols (CySH) abrogated the cytokine-stimulating activity of HMGB1 in cultured human primary macrophages and mouse macrophage-like RAW 264.7 cells (Yang H et al. 2012; Venereau E et al. 2012).

HMGB1 binding to LPS facilitated transfer of LPS to CD14 and enhanced TNFalpha production in human peripheral blood mononuclear cells (PBMCs) (Youn JH et al. 2008). HMGB1 in complex with LPS boosted proinflammatory cytokine- and matrix metalloproteinase (MMP3) production in synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients (Wähämaa H et al. 2011; He ZW et al. 2013).

In addition to its ability to act in a synergy with LPS and other ligands, HMGB1 was shown to stimulate cells by direct interaction with innate immune receptors such as TLR4:LY96 (Yang H et al. 2010; Yang H et al. 2015).

R-HSA-6805943 (Reactome) The human event of S100A1 is inferred from the mouse data.

S100A1 is a Ca(2+)-sensing protein of the EF-hand family. S100A1 is expressed predominantly in cardiomyocytes, where it regulates Ca(2+)-dependent signaling events (Wright NT et al. 2005; Cannon BR et al. 2011; Brinks H et al. 2011; Yu J et al. 2015; Rohde D et al. 2014; Ritterhoff J & Most P 2012). In response to ischemic/hypoxic damage of cardiomyocytes, S100A1 is released or transferred to the extracellular region through open channels on membrane (Rohde D et al. 2014). The extracellular S100A1 activates signal and promotes cell survival pathways, including inflammation response via Toll-like receptor 4 (TLR4) (Brinks H et al. 2011; Yu J et al. 2015; Rohde D et al. 2014). In rodent H9C2 cells S100A1 was found to regulate the inflammatory response and oxidative stress via TLR4/ROS/NFkappaB pathway ( Yu J et al. 2015).

R-HSA-6805981 (Reactome) High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein that under normal conditions binds and bends DNA and facilitates gene transcription. In response to infection or injury, HMGB1 is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells to function as alarmin (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Beyer C et al. 2012; Yang H et al. 2013). Earlier studies reported that HMGB1 did not diffuse out of cells undergoing apoptosis as HMGB1 was found to be tightly associated with the chromatin in apoptotic cells, even when the cell membrane was permeabilized artificially with detergents (Scaffidi P et al. 2002). This finding is in agreement with the general observation that apoptosis does not promote inflammation. However, further work showed that cells that undergo apoptosis do release HMGB1 (Bell CW et al. 2006; Yamada Y et al. 2011; Spencer DM et al. 2014). In human apoptotic cells (acute myeloid leukemia H60, HeLa, Jurkat T lymphocyte, pancreatic carcinoma PANC1 cell lines) HMGB1 was found to translocate into membrane-bound vesicles which are generated and released by cells during apoptosis (Spencer DM et al. 2014; Schiller M et al 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013).
R-HSA-8869667 (Reactome) Oxidized low-density lipoprotein (oxLDL) and amyloid-beta sequestered by the scavenger receptor CD36 trigger sterile inflammatory signaling through a CD36:TLR4:TLR6 heteromerization (Stewart CR et al., 2010). The heterotrimeric CD36:TLR4:TLR6 signaling complex, acting via NFkappaB and reactive oxygen species, primes the NLRP3 inflammasome in response to oxLDL (Sheedy FJ et al., 2013).
R-HSA-8869683 (Reactome) Antibacterial defence involves activation of neutrophils that generate reactive oxygen species (ROS) capable of killing bacteria. The ROS production results in the oxidation of host phospholipids. Endogenously formed oxidized phospholipids, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), have been shown to inhibit TLR4- & TLR2-mediated signaling induced by bacterial lipopeptide or lipopolysaccharide (LPS) in various human cells (Bochkov VN et al., 2002; von Schlieffen E et al., 2009). Oxidized phospholipids were found to bind LPS binding protein (LBP) and soluble CD14 suggesting that the binding prevented recognition of LPS by these proteins thus preventing recognition of LPS and activation of TLR4 (Erridge C et al., 2008; von Schlieffen E et al., 2009). In addition, oxPAPC protected mice treated with a lethal dose of LPS (Bochkov VN et al., 2002). Thus, oxidized phospholipids may function as a negative feedback to blunt innate immune responses.
R-HSA-8869694 (Reactome) The generation of reactive oxygen species is a central feature of inflammation that results in the oxidation of host phospholipids. Endogenously formed oxidized phospholipids, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), have been shown to inhibit TLR4- & TLR2-mediated signaling induced by bacterial lipopeptide or lipopolysaccharide (LPS) in various human cells (Bochkov VN et al., 2002; von Schlieffen E et al., 2009). Oxidized phospholipids were found to bind LPS binding protein (LBP) and soluble CD14 suggesting that the binding prevented recognition of LPS by these proteins thus preventing recognition of LPS and activation of TLR4 (Erridge C et al., 2008; von Schlieffen E et al., 2009). In addition, oxPAPC protected mice treated with a lethal dose of LPS (Bochkov VN et al., 2002). Thus, oxidized phospholipids may function as a negative feedback to blunt innate immune responses.
R-HSA-8870678 (Reactome) Fibrinogen, in addition to its role in coagulation, is also an acute phase protein of inflammation which can induce a cytokine production acting as an endogenous ligand for toll-like receptor 4 (TLR4) expressed on cells including macrophages and airway epithelial cells (Millien VO et al., 2013; Kuhns DB et al., 2007; Smiley ST et al., 2001). In human macrophages fibrinogen stimulated interleukin IL6 expression and extracellular signal-related kinase (ERK) phosphorylation ((Hodgkinson CP et al., 2008). In human embryonic kidney 293 (HEK293)-CD14-MD2 cells expressing TLR4, fibrinogen induced robust phosphorylation of ERK1, p38alpha and JNK and activated transcription factors NFkappaB, Elk1 and AP1 (Hodgkinson CP et al., 2008). Moreover, proteinases, such as thrombin, can cleave fibrinogen. In mice, exposure to endogenous or exogenous proteinases lead to hyperactivation of an antifungal pathway and lead to allergic airway inflammation through activation of TLR4-dependent signaling pathway by fibrinogen cleaved products (Millien VO et al., 2013)
S100A1 dimer:Ca(2+)R-HSA-6805943 (Reactome)
S100A1:TLR4:LY96ArrowR-HSA-6805943 (Reactome)
S100A8:S100A9R-HSA-5432849 (Reactome)
SFTPA oligomer, SFTPD oligomerR-HSA-5432814 (Reactome)
SFTPA oligomer, SFTPD oligomerR-HSA-5432852 (Reactome)
SFTPA/SFTPD:TLR2:TLR1ArrowR-HSA-5432814 (Reactome)
SP-A/SP-D:TLR4:MD2ArrowR-HSA-5432852 (Reactome)
TLR1:TLR2R-HSA-5432814 (Reactome)
TLR4:LY96:S100A8:S100A9ArrowR-HSA-5432849 (Reactome)
TLR4:LY96:cleaved fibrinogenArrowR-HSA-8870678 (Reactome)
TLR4:LY96R-HSA-5432825 (Reactome)
TLR4:LY96R-HSA-5432849 (Reactome)
TLR4:LY96R-HSA-5432852 (Reactome)
TLR4:LY96R-HSA-6805943 (Reactome)
TLR4:LY96R-HSA-8870678 (Reactome)
TLR4:TLR6:CD36:oxLDLArrowR-HSA-8869667 (Reactome)
TLR4:TLR6R-HSA-8869667 (Reactome)
oxLDL:CD36R-HSA-8869667 (Reactome)
oxidized phospholipidsR-HSA-8869683 (Reactome)
oxidized phospholipidsR-HSA-8869694 (Reactome)
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