Schematic representation of the three activation pathways of the complement system. All of the three pathways converge on the cleavage of C3 in C3a and C3b. C3b attaches to C3, becoming C5 convertase, which in turn cleaves C5, originating C5b. C5b, together with C6, C7, C8, and C9 forms the membrane attack complex. The Figure was created with BioRender software (https://biorender.com/). MASP: mannose-associated serine protease; MBL: mannose-binding lectin
Declarations
Author contributions
MS: Writing—original draft, Visualization. SP and CA: Writing—review & editing. RB: Conceptualization, Writing—review & editing, Supervision. All authors read and approved the submitted version.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Potlukova E, Kralikova P. Complement component c1q and anti-c1q antibodies in theory and in clinical practice.Scand J Immunol. 2008;67:423–30. [DOI] [PubMed]
Nayak A, Pednekar L, Reid KB, Kishore U. Complement and non-complement activating functions of C1q: a prototypical innate immune molecule.Innate Immun. 2012;18:350–63. [DOI] [PubMed]
Bonifati DM, Kishore U. Role of complement in neurodegeneration and neuroinflammation.Mol Immunol. 2007;44:999–1010. [DOI] [PubMed]
Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination.Cell. 2007;131:1164–78. [DOI] [PubMed]
Singh J, Ahmed A, Girardi G. Role of complement component C1q in the onset of preeclampsia in mice.Hypertension. 2011;58:716–24. [DOI] [PubMed]
Naito AT, Sumida T, Nomura S, Liu ML, Higo T, Nakagawa A, et al. Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes.Cell. 2012;149:1298–313.Erratum in: Cell. 2012;150:659–60. [DOI] [PubMed] [PMC]
Thielens NM, Tedesco F, Bohlson SS, Gaboriaud C, Tenner AJ. C1q: a fresh look upon an old molecule.Mol Immunol. 2017;89:73–83. [DOI] [PubMed] [PMC]
Kishore U, Gaboriaud C, Waters P, Shrive AK, Greenhough TJ, Reid KB, et al. C1q and tumor necrosis factor superfamily: modularity and versatility.Trends Immunol. 2004;25:551–61. [DOI] [PubMed]
Agostinis C, Mangogna A, Balduit A, Kishore U, Bulla R. A non-redundant role of complement protein C1q in normal and adverse pregnancy.Explor Immunol. 2022;2:622–36. [DOI]
Agostinis C, Tedesco F, Bulla R. Alternative functions of the complement protein C1q at embryo implantation site.J Reprod Immunol. 2017;119:74–80. [DOI] [PubMed]
Petry F, Botto M, Holtappels R, Walport MJ, Loos M. Reconstitution of the complement function in C1q-deficient (C1qa−/−) mice with wild-type bone marrow cells.J Immunol. 2001;167:4033–7. [DOI] [PubMed]
Ghebrehiwet B, Hosszu KK, Valentino A, Peerschke EI. The C1q family of proteins: insights into the emerging non-traditional functions.Front Immunol. 2012;3:52. [DOI] [PubMed] [PMC]
Bossi F, Tripodo C, Rizzi L, Bulla R, Agostinis C, Guarnotta C, et al. C1q as a unique player in angiogenesis with therapeutic implication in wound healing.Proc Natl Acad Sci U S A. 2014;111:4209–14. [DOI] [PubMed] [PMC]
Bulla R, Agostinis C, Bossi F, Rizzi L, Debeus A, Tripodo C, et al. Decidual endothelial cells express surface-bound C1q as a molecular bridge between endovascular trophoblast and decidual endothelium.Mol Immunol. 2008;45:2629–40. [DOI] [PubMed] [PMC]
Agostinis C, Bulla R, Tripodo C, Gismondi A, Stabile H, Bossi F, et al. An alternative role of C1q in cell migration and tissue remodeling: contribution to trophoblast invasion and placental development.J Immunol. 2010;185:4420–9. [DOI] [PubMed]
Ghai R, Waters P, Roumenina LT, Gadjeva M, Kojouharova MS, Reid KB, et al. C1q and its growing family.Immunobiology. 2007;212:253–66. [DOI] [PubMed]
Benoit ME, Clarke EV, Morgado P, Fraser DA, Tenner AJ. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells.J Immunol. 2012;188:5682–93. [DOI] [PubMed] [PMC]
Zwarthoff SA, Widmer K, Kuipers A, Strasser J, Ruyken M, Aerts PC, et al. C1q binding to surface-bound IgG is stabilized by C1r2s2 proteases.Proc Natl Acad Sci U S A. 2021;118:e2102787118. [DOI] [PubMed] [PMC]
Densen P, Ram S. Complement and deficiencies.In: Bennett JE, Dolin R, Blasér MJ, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 5th ed. Elsevier Inc.; 2015. pp. 93–115.
Laurell AB, Mårtensson U, Sjöholm AG. C1 dissociation. Spontaneous generation in human serum of a trimer complex containing C1 inactivator, activated C1r, and zymogen C1s.J Immunol. 1987;139:4145–51. [PubMed]
Nayak A, Ferluga J, Tsolaki AG, Kishore U. The non-classical functions of the classical complement pathway recognition subcomponent C1q.Immunol Lett. 2010;131:139–50. [DOI] [PubMed]
Ghebrehiwet B, Peerschke EI. Purification of C1q receptors and functional analysis.Methods Mol Biol. 2014;1100:319–27. [DOI] [PubMed]
Kahraman A, Karakulak T, Szklarczyk D, von Mering C. Pathogenic impact of transcript isoform switching in 1,209 cancer samples covering 27 cancer types using an isoform-specific interaction network.Sci Rep. 2020;10:14453. [DOI] [PubMed] [PMC]
Malhotra R, Willis AC, Jensenius JC, Jackson J, Sim RB. Structure and homology of human C1q receptor (collectin receptor).Immunology. 1993;78:341–8. [PubMed] [PMC]
Ghebrehiwet B, Lim BL, Peerschke EI, Willis AC, Reid KB. Isolation, cDNA cloning, and overexpression of a 33-kD cell surface glycoprotein that binds to the globular “heads” of C1q.J Exp Med. 1994;179:1809–21. [DOI] [PubMed] [PMC]
Ogden CA, deCathelineau A, Hoffmann PR, Bratton D, Ghebrehiwet B, Fadok VA, et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells.J Exp Med. 2001;194:781–96. [DOI] [PubMed] [PMC]
Vandivier RW, Ogden CA, Fadok VA, Hoffmann PR, Brown KK, Botto M, et al. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex.J Immunol. 2002;169:3978–86. [DOI] [PubMed]
Ghiran I, Klickstein LB, Nicholson-Weller A. Calreticulin is at the surface of circulating neutrophils and uses CD59 as an adaptor molecule.J Biol Chem. 2003;278:21024–31. [DOI] [PubMed]
Hosszu KK, Valentino A, Vinayagasundaram U, Vinayagasundaram R, Joyce MG, Ji Y, et al. DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells.Blood. 2012;120:1228–36. [DOI] [PubMed] [PMC]
Fearon DT. Identification of the membrane glycoprotein that is the C3b receptor of the human erythrocyte, polymorphonuclear leukocyte, B lymphocyte, and monocyte.J Exp Med. 1980;152:20–30. [DOI] [PubMed] [PMC]
Jacquet M, Cioci G, Fouet G, Bally I, Thielens NM, Gaboriaud C, et al. C1q and mannose-binding lectin interact with CR1 in the same region on CCP24-25 modules.Front Immunol. 2018;9:453. [DOI] [PubMed] [PMC]
Ghebrehiwet B, Habicht GS, Beck G. Interaction of C1q with its receptor on cultured cell lines induces an anti-proliferative response.Clin Immunol Immunopathol. 1990;54:148–60. [DOI] [PubMed]
Feng X, Tonnesen MG, Peerschke EI, Ghebrehiwet B. Cooperation of C1q receptors and integrins in C1q-mediated endothelial cell adhesion and spreading.J Immunol. 2002;168:2441–8. [DOI] [PubMed]
Castellano G, Woltman AM, Nauta AJ, Roos A, Trouw LA, Seelen MA, et al. Maturation of dendritic cells abrogates C1q production in vivo and in vitro.Blood. 2004;103:3813–20. [DOI] [PubMed]
Hosszu KK, Santiago-Schwarz F, Peerschke EI, Ghebrehiwet B. Evidence that a C1q/C1qR system regulates monocyte-derived dendritic cell differentiation at the interface of innate and acquired immunity.Innate Immun. 2010;16:115–27. [DOI] [PubMed] [PMC]
Kuna P, Iyer M, Peerschke EI, Kaplan AP, Reid KB, Ghebrehiwet B. Human C1q induces eosinophil migration.Clin Immunol Immunopathol. 1996;81:48–54. [DOI] [PubMed]
Leigh LE, Ghebrehiwet B, Perera TP, Bird IN, Strong P, Kishore U, et al. C1q-mediated chemotaxis by human neutrophils: involvement of gClqR and G-protein signalling mechanisms.Biochem J. 1998;330:247–54. [DOI] [PubMed] [PMC]
Vegh Z, Kew RR, Gruber BL, Ghebrehiwet B. Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR.Mol Immunol. 2006;43:1402–7. [DOI] [PubMed]
Risau W, Flamme I. Vasculogenesis.Annu Rev Cell Dev Biol. 1995;11:73–91. [DOI] [PubMed]
Markiewski MM, Daugherity E, Reese B, Karbowniczek M. The role of complement in angiogenesis.Antibodies (Basel). 2020;9:67. [DOI] [PubMed] [PMC]
Félétou M. The endothelium, part I: multiple functions of the endothelial cells – focus on endothelium-derived vasoactive mediators. In: Granger DN, Granger JP, editors. Integrated systems physiology: from molecule to function to disease. San Rafael (CA): Morgan & Claypool Life Sciences; 2011. pp. 1–306. [DOI] [PubMed]
Asahara T, Kawamoto A. Endothelial progenitor cells for postnatal vasculogenesis.Am J Physiol Cell Physiol. 2004;287:C572–9. [DOI] [PubMed]
Carmeliet P. Angiogenesis in health and disease.Nat Med. 2003;9:653–60. [DOI] [PubMed]
Eelen G, Treps L, Li X, Carmeliet P. Basic and therapeutic aspects of angiogenesis updated.Circ Res. 2020;127:310–29. [DOI] [PubMed]
Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation.Sci Transl Med. 2014;6:265sr6. [DOI] [PubMed] [PMC]
Yetkin-Arik B, Kastelein AW, Klaassen I, Jansen C, Latul YP, Vittori M, et al. Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapy.Biochim Biophys Acta Rev Cancer. 2021;1875:188446. [DOI] [PubMed]
Gianni-Barrera R, Butschkau A, Uccelli A, Certelli A, Valente P, Bartolomeo M, et al. PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation.Angiogenesis. 2018;21:883–900. [DOI] [PubMed] [PMC]
Makanya AN, Hlushchuk R, Djonov VG. Intussusceptive angiogenesis and its role in vascular morphogenesis, patterning, and remodeling.Angiogenesis. 2009;12:113–23. [DOI] [PubMed]
De Spiegelaere W, Casteleyn C, Van den Broeck W, Plendl J, Bahramsoltani M, Simoens P, et al. Intussusceptive angiogenesis: a biologically relevant form of angiogenesis.J Vasc Res. 2012;49:390–404.Erratum in: J Vasc Res. 2012;49:416. [DOI] [PubMed]
Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis.Cell. 2011;146:873–87. [DOI] [PubMed]
Arroyo AG, Iruela-Arispe ML. Extracellular matrix, inflammation, and the angiogenic response.Cardiovasc Res. 2010;86:226–35. [DOI] [PubMed] [PMC]
Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch.Dev Cell. 2009;16:196–208. [DOI] [PubMed]
Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling.Nat Rev Mol Cell Biol. 2016;17:611–25. [DOI] [PubMed]
Abhinand CS, Raju R, Soumya SJ, Arya PS, Sudhakaran PR. VEGF-A/VEGFR2 signaling network in endothelial cells relevant to angiogenesis.J Cell Commun Signal. 2016;10:347–54. [DOI] [PubMed] [PMC]
Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.Nat Med. 2001;7:575–83. [DOI] [PubMed]
De Falco S, Gigante B, Persico MG. Structure and function of placental growth factor.Trends Cardiovasc Med. 2002;12:241–6. [DOI] [PubMed]
Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J. Comparative evaluation of FGF-2–, VEGF-A–, and VEGF-C–induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability.Circ Res. 2004;94:664–70. [DOI] [PubMed]
Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI, et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses.Circ Res. 2003;92:1098–106. [DOI] [PubMed]
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors.Nat Med. 2003;9:669–76. [DOI] [PubMed]
Watanabe Y, Lee SW, Detmar M, Ajioka I, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) delays and induces escape from senescence in human dermal microvascular endothelial cells.Oncogene. 1997;14:2025–32. [DOI] [PubMed]
Braile M, Marcella S, Cristinziano L, Galdiero MR, Modestino L, Ferrara AL, et al. VEGF-A in cardiomyocytes and heart diseases.Int J Mol Sci. 2020;21:5294. [DOI] [PubMed] [PMC]
Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.Cell. 1998;92:735–45. [DOI] [PubMed]
Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.Am J Pathol. 1995;146:1029–39. [PubMed] [PMC]
Folkman J. Role of angiogenesis in tumor growth and metastasis.Semin Oncol. 2002;29:15–8. [DOI] [PubMed]
Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.J Clin Invest. 2003;111:649–58. [DOI] [PubMed] [PMC]
Winther H, Ahmed A, Dantzer V. Immunohistochemical localization of vascular endothelial growth factor (VEGF) and its two specific receptors, Flt-1 and KDR, in the porcine placenta and non-pregnant uterus.Placenta. 1999;20:35–43. [DOI] [PubMed]
Clauss M, Gerlach M, Gerlach H, Brett J, Wang F, Familletti PC, et al. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration.J Exp Med. 1990;172:1535–45. [DOI] [PubMed] [PMC]
Miao HQ, Lee P, Lin H, Soker S, Klagsbrun M. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression.FASEB J. 2000;14:2532–9. [DOI] [PubMed]
Park JE, Chen HH, Winer J, Houck KA, Ferrara N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR.J Biol Chem. 1994;269:25646–54. [DOI] [PubMed]
Yonekura H, Sakurai S, Liu X, Migita H, Wang H, Yamagishi S, et al. Placenta growth factor and vascular endothelial growth factor B and C expression in microvascular endothelial cells and pericytes.J Biol Chem. 1999;274:35172–8. [DOI] [PubMed]
Rafii S, Avecilla S, Shmelkov S, Shido K, Tejada R, Moore MA, et al. Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment.Ann N Y Acad Sci. 2003;996:49–60. [DOI] [PubMed]
Selvaraj SK, Giri RK, Perelman N, Johnson C, Malik P, Kalra VK. Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor.Blood. 2003;102:1515–24. [DOI] [PubMed]
Roy H, Bhardwaj S, Babu M, Jauhiainen S, Herzig KH, Bellu AR, et al. Adenovirus-mediated gene transfer of placental growth factor to perivascular tissue induces angiogenesis via upregulation of the expression of endogenous vascular endothelial growth factor-A.Hum Gene Ther. 2005;16:1422–8. [DOI] [PubMed]
Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity.Cold Spring Harb Perspect Med. 2012;2:a011056. [DOI] [PubMed] [PMC]
Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system.Nat Rev Mol Cell Biol. 2009;10:165–77. [DOI] [PubMed]
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation.Nature. 2000;407:242–8. [DOI] [PubMed]
Michiels C. Endothelial cell functions.J Cell Physiol. 2003;196:430–43. [DOI] [PubMed]
Kim I, Kim HG, So JN, Kim JH, Kwak HJ, Koh GY. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway.Circ Res. 2000;86:24–9. [DOI] [PubMed]
Potente M, Urbich C, Sasaki K, Hofmann WK, Heeschen C, Aicher A, et al. Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization.J Clin Invest. 2005;115:2382–92. [DOI] [PubMed] [PMC]
Yuan HT, Khankin EV, Karumanchi SA, Parikh SM. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium.Mol Cell Biol. 2009;29:2011–22.Erratum in: Mol Cell Biol. 2009;29:3451. [DOI] [PubMed] [PMC]
Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells.J Biol Chem. 1999;274:15732–9. [DOI] [PubMed]
Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.Science. 1997;277:55–60. [DOI] [PubMed]
Kim M, Allen B, Korhonen EA, Nitschké M, Yang HW, Baluk P, et al. Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation.J Clin Invest. 2016;126:3511–25. [DOI] [PubMed] [PMC]
Brunn GJ, Saadi S, Platt JL. Differential regulation of endothelial cell activation by complement and interleukin 1α.Circ Res. 2006;98:793–800. [DOI] [PubMed] [PMC]
Tedesco F, Fischetti F, Pausa M, Dobrina A, Sim RB, Daha MR. Complement-endothelial cell interactions: pathophysiological implications: [Mol. Immunol. (1999) 36(4-5) 261-268].Mol Immunol. 2000;37:91. [DOI] [PubMed]
Masat E, Gasparini C, Agostinis C, Bossi F, Radillo O, De Seta F, et al. RelB activation in anti-inflammatory decidual endothelial cells: a master plan to avoid pregnancy failure?Sci Rep. 2015;5:14847. [DOI] [PubMed] [PMC]
Fan G, Li Q, Qian J. C1q contributes to post-stroke angiogenesis via LAIR1-HIF1α-VEGF pathway.Front Biosci (Landmark Ed). 2019;24:1050–9. [DOI] [PubMed]
Bulla R, Tripodo C, Rami D, Ling GS, Agostinis C, Guarnotta C, et al. C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation.Nat Commun. 2016;7:10346. [DOI] [PubMed] [PMC]
Agostinis C, Spazzapan M, Vuerich R, Balduit A, Stocco C, Mangogna A, et al. Differential capability of clinically employed dermal regeneration scaffolds to support vascularization for tissue bioengineering.Biomedicines. 2021;9:1458. [DOI] [PubMed] [PMC]
Przekora A. A concise review on tissue engineered artificial skin grafts for chronic wound treatment: can we reconstruct functional skin tissue in vitro?Cells. 2020;9:1622. [DOI] [PubMed] [PMC]
van den Berg RH, Faber-Krol MC, Sim RB, Daha MR. The first subcomponent of complement, C1q, triggers the production of IL-8, IL-6, and monocyte chemoattractant peptide-1 by human umbilical vein endothelial cells.J Immunol. 1998;161:6924–30. [DOI] [PubMed]
Navratil JS, Watkins SC, Wisnieski JJ, Ahearn JM. The globular heads of C1q specifically recognize surface blebs of apoptotic vascular endothelial cells.J Immunol. 2001;166:3231–9. [DOI] [PubMed]
Carmeliet P. Angiogenesis in life, disease and medicine.Nature. 2005;438:932–6. [DOI] [PubMed]
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis.Nature. 2011;473:298–307. [DOI] [PubMed] [PMC]
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N Engl J Med. 2004;350:2335–42. [DOI] [PubMed]
Orlandini M, Galvagni F, Bardelli M, Rocchigiani M, Lentucci C, Anselmi F, et al. The characterization of a novel monoclonal antibody against CD93 unveils a new antiangiogenic target.Oncotarget. 2014;5:2750–60. [DOI] [PubMed] [PMC]
Galvagni F, Nardi F, Maida M, Bernardini G, Vannuccini S, Petraglia F, et al. CD93 and dystroglycan cooperation in human endothelial cell adhesion and migration adhesion and migration.Oncotarget. 2016;7:10090–103. [DOI] [PubMed] [PMC]
McGreal E, Gasque P. Structure-function studies of the receptors for complement C1q.Biochem Soc Trans. 2002;30:1010–4. [DOI] [PubMed]
Mangogna A, Agostinis C, Bonazza D, Belmonte B, Zacchi P, Zito G, et al. Is the complement protein C1q a pro- or anti-tumorigenic factor? Bioinformatics analysis involving human carcinomas.Front Immunol. 2019;10:865. [DOI] [PubMed] [PMC]
