Fibrin Complement Receptor 3 Signaling Pathway (Homo sapiens)

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32225, 10238, 911227NucleusMacrophageCytoskeletal rearrangementFibrin DegradationProductsMyD88-dependentDegradationdsRNALigand-independentsignalingNF-kBTIRAPTRIFFcRgPlasminogentPADAP12LPSCXCL3IL6CBL-BIKBKBRAPLTRAF6CD14Blood Clotting CascadeCXCL10SYKIRAK1AKT1FibrinPI3KTLR3IFNB1MYD88RHOAPlasminPIRAK4MD2LBPTLR4SRCTRAFIRF3P2CD11bCD18Phagocytosis4, 6TRIFPMYD88P3TNFSYKIRF3PCCL27NF-kBCHUKIKBKGPI3KMyD88-independentFibrinogenIRAK2IL12BNOS2


Description

The blood protein fibrinogen, a key component of the coagulation cascade, has been identified as an early molecular factor triggering inflammation in the brain and periphery (see bibliography). Upon fibrinogen extravasation across leaky vessels (i.e., break down of the blood-brain barrier), fibrinogen is converted by thrombin to insoluble fibrin. Based on published studies, this signaling pathway highlights fibrin as a CD11b/CD18 (complement receptor; CR3) integrin receptor ligand that regulates innate immunity. Fibrin activates central nervous system (CNS) resident microglia and peripheral (bone marrow derived) macrophages via CR3, leading to intracellular kinase signaling activation including PI3K, AKT1 and RhoA activity that regulates phagocytosis; and NF-κB translocation to the nucleus that transcriptionally regulates proinflammatory cytokines and chemokines that recruit T-cells and macrophages. Canonical LPS-TLR4 activation of innate immune cells and potential mechanisms of CD11b transactivation are shown.

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Bibliography

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  1. Caron E, Hall A; ''Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases.''; Science, 1998 PubMed
  2. Han C, Jin J, Xu S, Liu H, Li N, Cao X; ''Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b.''; Nat Immunol, 2010 PubMed
  3. Ryu JK, Petersen MA, Murray SG, Baeten KM, Meyer-Franke A, Chan JP, Vagena E, Bedard C, Machado MR, Rios Coronado PE, Prod'homme T, Charo IF, Lassmann H, Degen JL, Zamvil SS, Akassoglou K; ''Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation.''; Nat Commun, 2015 PubMed
  4. Flick MJ, Du X, Witte DP, Jirousková M, Soloviev DA, Busuttil SJ, Plow EF, Degen JL; ''Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo.''; J Clin Invest, 2004 PubMed
  5. Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, Degen JL, Akassoglou K; ''The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease.''; J Exp Med, 2007 PubMed
  6. Stephens L, Ellson C, Hawkins P; ''Roles of PI3Ks in leukocyte chemotaxis and phagocytosis.''; Curr Opin Cell Biol, 2002 PubMed
  7. Means TK, Luster AD; ''Integrins limit the Toll.''; Nat Immunol, 2010 PubMed
  8. Ugarova TP, Lishko VK, Podolnikova NP, Okumura N, Merkulov SM, Yakubenko VP, Yee VC, Lord ST, Haas TA; ''Sequence gamma 377-395(P2), but not gamma 190-202(P1), is the binding sitefor the alpha MI-domain of integrin alpha M beta 2 in the gamma C-domain of fibrinogen.''; Biochemistry, 2003 PubMed
  9. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO; ''The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex.''; Nature, 2009 PubMed
  10. Perez RL, Roman J; ''Fibrin enhances the expression of IL-1 beta by human peripheral blood mononuclear cells. Implications in pulmonary inflammation.''; J Immunol, 1995 PubMed
  11. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B; ''Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.''; Science, 1998 PubMed

History

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CompareRevisionActionTimeUserComment
98484view17:31, 11 September 2018Khanspersfixed broken literature reference
96449view09:27, 15 March 2018EgonwReplaced a secondary ChEBI identifier with a primary identifier.
95528view17:24, 20 December 2017Khanspersfixed unconnected
95522view18:16, 19 December 2017Khanspersupdated xref for PI3K
95521view17:55, 19 December 2017KhanspersOntology Term : 'coagulation cascade pathway' added !
95520view17:53, 19 December 2017KhanspersOntology Term : 'classical complement pathway' added !
95519view17:52, 19 December 2017KhanspersOntology Term : 'inflammatory response pathway' added !
95518view17:51, 19 December 2017KhanspersOntology Term : 'microglial cell' added !
95517view17:50, 19 December 2017KhanspersOntology Term : 'macrophage' added !
95515view02:24, 19 December 2017AkassoglouModified description
95514view02:23, 19 December 2017AkassoglouModified description
95513view02:23, 19 December 2017AkassoglouModified title
94852view23:11, 9 October 2017Khansperslayout update
94302view05:18, 1 September 2017KhanspersOntology Term : 'microglial cell' added !
94278view18:43, 30 August 2017AndrewmendiolaModified description
93729view23:57, 15 August 2017KhanspersNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1GeneProductENSG00000142208 (Ensembl)
Blood Clotting CascadePathwayWP272 (WikiPathways)
CBL-BProteinE9PHA9 (Uniprot-TrEMBL)
CCL2GeneProductENSG00000108691 (Ensembl)
CD11bGeneProductENSG00000169896 (Ensembl)
CD14GeneProductENSG00000170458 (Ensembl)
CD18GeneProductENSG00000160255 (Ensembl)
CHUKGeneProductENSG00000213341 (Ensembl)
CXCL10GeneProductENSG00000169245 (Ensembl)
CXCL3GeneProductENSG00000163734 (Ensembl)
DAP12GeneProductENSG00000011600 (Ensembl)
FcRgGeneProduct
FibrinMetaboliteCHEBI:5054 (ChEBI)
FibrinogenGeneProduct
IFNB1GeneProductENSG00000171855 (Ensembl)
IKBKBGeneProductENSG00000104365 (Ensembl)
IKBKGGeneProductENSG00000269335 (Ensembl)
IL12BGeneProductENSG00000113302 (Ensembl)
IL6GeneProductENSG00000136244 (Ensembl)
IRAK1GeneProductENSG00000184216 (Ensembl)
IRAK2GeneProductENSG00000134070 (Ensembl)
IRAK4GeneProductENSG00000198001 (Ensembl)
IRF3GeneProductENSG00000126456 (Ensembl)
LBPGeneProductENSG00000129988 (Ensembl)
LPSMetaboliteCHEBI:16412 (ChEBI)
MD2GeneProductENSG00000154589 (Ensembl)
MYD88GeneProductENSG00000172936 (Ensembl)
NF-kBGeneProductENSG00000109320 (Ensembl)
NF-kBGeneProduct
NOS2GeneProductENSG00000007171 (Ensembl)
PI3KGeneProduct
PI3KGeneProductQ423725 (Wikidata)
PlasminGeneProductENSG00000122194 (Ensembl)
PlasminogenGeneProductENSG00000122194 (Ensembl)
RAPLGeneProductENSG00000266094 (Ensembl)
RHOAGeneProductENSG00000067560 (Ensembl)
SRCGeneProductENSG00000197122 (Ensembl)
SYKGeneProductENSG00000165025 (Ensembl)
TIRAPGeneProductENSG00000150455 (Ensembl)
TLR3GeneProductENSG00000164342 (Ensembl)
TLR4GeneProductENSG00000136869 (Ensembl)
TNFGeneProductENSG00000232810 (Ensembl)
TRAF6GeneProductENSG00000175104 (Ensembl)
TRAFGeneProductENSG00000243414 (Ensembl)
TRIFGeneProductENSG00000127666 (Ensembl)
tPAGeneProductENSG00000104368 (Ensembl)

Annotated Interactions

No annotated interactions

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