Fibrin complement receptor 3 signaling pathway (WP4136)

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. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP4136 CPTAC Assay Portal]
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Authors

Khanspers, Andrewmendiola, Akassoglou, Egonw, AlexanderPico, Eweitz, and Mkutmon

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: coagulation cascade pathway coagulation cascade pathway classical complement pathway inflammatory response pathway inflammatory response pathway classical complement pathway

Cell Type Ontology: macrophage microglial cell microglial cell

Participants

Label Type Compact Identifier
AKT1 GeneProduct ensembl:ENSG00000142208
IL6 GeneProduct ensembl:ENSG00000136244
IKBKB GeneProduct ensembl:ENSG00000104365
PI3K GeneProduct ncbigene:5290
Plasminogen GeneProduct ensembl:ENSG00000122194
SYK GeneProduct ensembl:ENSG00000165025
LPS Metabolite chebi:16412
TLR3 GeneProduct ensembl:ENSG00000164342
CBL-B GeneProduct ensembl:ENSG00000114423
MYD88 GeneProduct ensembl:ENSG00000172936
IFNB1 GeneProduct ensembl:ENSG00000171855
RHOA GeneProduct ensembl:ENSG00000067560
Blood Clotting Cascade Pathway wikipathways:WP272
IRAK1 GeneProduct ensembl:ENSG00000184216
tPA GeneProduct ensembl:ENSG00000104368
CXCL10 GeneProduct ensembl:ENSG00000169245
RAPL GeneProduct ensembl:ENSG00000266094
Fibrin Metabolite chebi:5054
NFKB1 GeneProduct ensembl:ENSG00000109320
TIRAP GeneProduct ensembl:ENSG00000150455
TRAF6 GeneProduct ensembl:ENSG00000175104
TRIF GeneProduct ensembl:ENSG00000127666
CD14 GeneProduct ensembl:ENSG00000170458
DAP12 GeneProduct ensembl:ENSG00000011600
FcRg GeneProduct None
CXCL3 GeneProduct ensembl:ENSG00000163734
Plasmin GeneProduct ensembl:ENSG00000122194
IRAK4 GeneProduct ensembl:ENSG00000198001
MD2 GeneProduct ensembl:ENSG00000154589
LBP GeneProduct ensembl:ENSG00000129988
TLR4 GeneProduct ensembl:ENSG00000136869
SRC GeneProduct ensembl:ENSG00000197122
TRAF GeneProduct ensembl:ENSG00000243414
IRF3 GeneProduct ensembl:ENSG00000126456
CD11b GeneProduct ensembl:ENSG00000169896
CD18 GeneProduct ensembl:ENSG00000160255
TRIF GeneProduct ensembl:ENSG00000127666
MYD88 GeneProduct ensembl:ENSG00000172936
TNF GeneProduct ensembl:ENSG00000232810
SYK GeneProduct ensembl:ENSG00000165025
IRF3 GeneProduct ensembl:ENSG00000126456
CCL2 GeneProduct ensembl:ENSG00000108691
CHUK GeneProduct ensembl:ENSG00000213341
IKBKG GeneProduct ensembl:ENSG00000269335
PI3K GeneProduct ncbigene:5290
FGA GeneProduct ensembl:ENSG00000171560
IRAK2 GeneProduct ensembl:ENSG00000134070
IL12B GeneProduct ensembl:ENSG00000113302
NOS2 GeneProduct ensembl:ENSG00000007171
FGB GeneProduct ensembl:ENSG00000171564
FGG GeneProduct ensembl:ENSG00000171557
REL GeneProduct ensembl:ENSG00000162924
RELA GeneProduct ensembl:ENSG00000173039
NFKB1 GeneProduct ensembl:ENSG00000109320
REL GeneProduct ensembl:ENSG00000162924
RELA GeneProduct ensembl:ENSG00000173039

References

  1. Caron E, Hall A. Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science. 1998 Nov 27;282(5394):1717–21. PubMed Europe PMC Scholia
  2. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998 Dec 11;282(5396):2085–8. PubMed Europe PMC Scholia
  3. Stephens L, Ellson C, Hawkins P. Roles of PI3Ks in leukocyte chemotaxis and phagocytosis. Curr Opin Cell Biol. 2002 Apr;14(2):203–13. PubMed Europe PMC Scholia
  4. Ugarova TP, Lishko VK, Podolnikova NP, Okumura N, Merkulov SM, Yakubenko VP, et al. Sequence gamma 377-395(P2), but not gamma 190-202(P1), is the binding site for the alpha MI-domain of integrin alpha M beta 2 in the gamma C-domain of fibrinogen. Biochemistry. 2003 Aug 12;42(31):9365–73. PubMed Europe PMC Scholia
  5. Flick MJ, Du X, Witte DP, Jirousková M, Soloviev DA, Busuttil SJ, et al. Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo. J Clin Invest. 2004 Jun;113(11):1596–606. PubMed Europe PMC Scholia
  6. Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, et al. The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med. 2007 Mar 19;204(3):571–82. PubMed Europe PMC Scholia
  7. Park BS, Song DH, Kim HM, Choi B-S, Lee H, Lee J-O. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature. 2009 Apr 30;458(7242):1191–5. PubMed Europe PMC Scholia
  8. 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 Aug;11(8):734–42. PubMed Europe PMC Scholia
  9. Means TK, Luster AD. Integrins limit the Toll. Nat Immunol. 2010 Aug;11(8):691–3. PubMed Europe PMC Scholia
  10. Ryu JK, Petersen MA, Murray SG, Baeten KM, Meyer-Franke A, Chan JP, et al. Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat Commun. 2015 Sep 10;6:8164. PubMed Europe PMC Scholia