Fibrin complement receptor 3 signaling pathway (Mus musculus)

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18888823, 10176, 98NucleusMacrophageFibrinogenCytoskeletal rearrangementMyD88-dependentdsRNALigand-independentsignalingFibrin DegradationProductsDegradationTlr3Dap12LPSNfkb1PlasminogenTRIFCxcl3Blood Clotting CascadeIfnb1IkbkbtPaSykRhoaRelIrak1Myd88Traf6FibrinTirapIl6RaplCxcl10Cd14Akt1Pik3caCbl-bFcRgPlasminPIrak4MD2LbpTlr4SrcTRAMIrf3P8Cd11bCd18Phagocytosis4, 5TRIFMyd88PP1TnfSykIrf3PCcl27ChukIkbkgPik3caMyD88-independentFgaIrak2Il12bNos2FgbFggRelaNfkb1RelRela


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.

This pathway has been converted from human to mouse from

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  1. 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 Europe PMC Scholia
  2. 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 Europe PMC Scholia
  3. 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 Europe PMC Scholia
  4. Stephens L, Ellson C, Hawkins P; ''Roles of PI3Ks in leukocyte chemotaxis and phagocytosis.''; Curr Opin Cell Biol, 2002 PubMed Europe PMC Scholia
  5. Caron E, Hall A; ''Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases.''; Science, 1998 PubMed Europe PMC Scholia
  6. 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 Europe PMC Scholia
  7. 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 Europe PMC Scholia
  8. Means TK, Luster AD; ''Integrins limit the Toll.''; Nat Immunol, 2010 PubMed Europe PMC Scholia
  9. 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 Europe PMC Scholia
  10. 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 Europe PMC Scholia


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120386view08:11, 30 November 2021EgonwMade another pathway clickable
119722view15:07, 8 August 2021KhanspersModified description
119689view19:07, 29 July 2021KhanspersModified description
119688view19:06, 29 July 2021KhanspersModified description
119687view19:05, 29 July 2021KhanspersNew pathway

External references


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NameTypeDatabase referenceComment
Akt1GeneProductENSMUSG00000001729 (Ensembl)
Blood Clotting CascadePathwayWP272 (WikiPathways)
Cbl-bGeneProductENSMUSG00000022637 (Ensembl)
Ccl2GeneProductENSMUSG00000035385 (Ensembl)
Cd11bGeneProductENSMUSG00000030786 (Ensembl)
Cd14GeneProductENSMUSG00000051439 (Ensembl)
Cd18GeneProductENSMUSG00000000290 (Ensembl)
ChukGeneProductENSMUSG00000025199 (Ensembl)
Cxcl10GeneProductENSMUSG00000034855 (Ensembl)
Cxcl3GeneProductENSMUSG00000029379 (Ensembl)
Dap12GeneProductENSMUSG00000030579 (Ensembl)
FcRgGeneProductENSMUSG00000058715 (Ensembl)
FgaGeneProductENSMUSG00000028001 (Ensembl)
FgbGeneProductENSMUSG00000033831 (Ensembl)
FggGeneProductENSMUSG00000033860 (Ensembl)
FibrinMetaboliteCHEBI:5054 (ChEBI)
Ifnb1GeneProductENSMUSG00000048806 (Ensembl)
IkbkbGeneProductENSMUSG00000031537 (Ensembl)
IkbkgGeneProductENSMUSG00000004221 (Ensembl)
Il12bGeneProductENSMUSG00000004296 (Ensembl)
Il6GeneProductENSMUSG00000025746 (Ensembl)
Irak1GeneProductENSMUSG00000031392 (Ensembl)
Irak2GeneProductENSMUSG00000060477 (Ensembl)
Irak4GeneProductENSMUSG00000059883 (Ensembl)
Irf3GeneProductENSMUSG00000003184 (Ensembl)
LPSMetaboliteCHEBI:16412 (ChEBI)
LbpGeneProductENSMUSG00000016024 (Ensembl)
MD2GeneProductENSMUSG00000025779 (Ensembl)
Myd88GeneProductENSMUSG00000032508 (Ensembl)
Nfkb1GeneProductENSMUSG00000028163 (Ensembl)
Nos2GeneProductENSMUSG00000020826 (Ensembl)
Pik3caGeneProductENSMUSG00000027665 (Ensembl)
PlasminGeneProductENSMUSG00000059481 (Ensembl)
PlasminogenGeneProductENSMUSG00000059481 (Ensembl)
RaplGeneProductENSMUSG00000026430 (Ensembl)
RelGeneProductENSMUSG00000020275 (Ensembl)
RelaGeneProductENSMUSG00000024927 (Ensembl)
RhoaGeneProductENSMUSG00000007815 (Ensembl)
SrcGeneProductENSMUSG00000027646 (Ensembl)
SykGeneProductENSMUSG00000021457 (Ensembl)
TRAMGeneProductENSMUSG00000056130 (Ensembl)
TRIFGeneProductENSMUSG00000047123 (Ensembl)
TirapGeneProductENSMUSG00000032041 (Ensembl)
Tlr3GeneProductENSMUSG00000031639 (Ensembl)
Tlr4GeneProductENSMUSG00000039005 (Ensembl)
TnfGeneProductENSMUSG00000024401 (Ensembl)
Traf6GeneProductENSMUSG00000027164 (Ensembl)
tPaGeneProductENSMUSG00000031538 (Ensembl)

Annotated Interactions

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