Fibrin complement receptor 3 signaling (WP4136)
Homo sapiens
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]
Authors
Kristina Hanspers , Andrew Mendiola , Katerina Akassoglou , Egon Willighagen , Alex Pico , Eric Weitz , and Martina Summer-KutmonActivity
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Cited In
- Investigating the Molecular Processes behind the Cell-Specific Toxicity Response to Titanium Dioxide Nanobelts (2021).
- LMWF5A suppresses cytokine release by modulating select inflammatory transcription factor activity in stimulated PBMC (2020).
- Construction and analysis of protein-protein interaction network of non-alcoholic fatty liver disease.
- In silico transcriptional analysis of asymptomatic and severe COVID-19 patients reveals the susceptibility of severe patients to other comorbidities and non-viral pathological conditions (2023).
- The differential expression of adipose tissue genes in short, medium and long-term periods after bariatric surgery (2024).
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Organisms
Homo sapiensCommunities
Annotations
Pathway Ontology
coagulation cascade pathway inflammatory response pathway classical complement pathway inflammatory response pathway classical complement pathway coagulation cascade pathwayCell Type Ontology
microglial cell microglial cell macrophageReferences
- Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Caron E, Hall A. Science. 1998 Nov 27;282(5394):1717–21. PubMed Europe PMC Scholia
- Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Science. 1998 Dec 11;282(5396):2085–8. PubMed Europe PMC Scholia
- Roles of PI3Ks in leukocyte chemotaxis and phagocytosis. Stephens L, Ellson C, Hawkins P. Curr Opin Cell Biol. 2002 Apr;14(2):203–13. PubMed Europe PMC Scholia
- 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. Ugarova TP, Lishko VK, Podolnikova NP, Okumura N, Merkulov SM, Yakubenko VP, et al. Biochemistry. 2003 Aug 12;42(31):9365–73. PubMed Europe PMC Scholia
- Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo. Flick MJ, Du X, Witte DP, Jirousková M, Soloviev DA, Busuttil SJ, et al. J Clin Invest. 2004 Jun;113(11):1596–606. PubMed Europe PMC Scholia
- The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, et al. J Exp Med. 2007 Mar 19;204(3):571–82. PubMed Europe PMC Scholia
- The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO. Nature. 2009 Apr 30;458(7242):1191–5. PubMed Europe PMC Scholia
- Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Han C, Jin J, Xu S, Liu H, Li N, Cao X. Nat Immunol. 2010 Aug;11(8):734–42. PubMed Europe PMC Scholia
- Integrins limit the Toll. Means TK, Luster AD. Nat Immunol. 2010 Aug;11(8):691–3. PubMed Europe PMC Scholia
- Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Ryu JK, Petersen MA, Murray SG, Baeten KM, Meyer-Franke A, Chan JP, et al. Nat Commun. 2015 Sep 10;6:8164. PubMed Europe PMC Scholia