Complement: A novel factor in basal and ischemia-induced neurogenesis

Institute of Biomedicine, Department of Medical Chemistry and Cell Biology, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
The EMBO Journal (Impact Factor: 10.43). 04/2006; 25(6):1364-74. DOI: 10.1038/sj.emboj.7601004
Source: PubMed


Through its involvement in inflammation, opsonization, and cytolysis, the complement protects against infectious agents. Although most of the complement proteins are synthesized in the central nervous system (CNS), the role of the complement system in the normal or ischemic CNS remains unclear. Here we demonstrate for the first time that neural progenitor cells and immature neurons express receptors for complement fragments C3a and C5a (C3a receptor (C3aR) and C5a receptor). Mice that are deficient in complement factor C3 (C3(-/-)) lack C3a and are unable to generate C5a through proteolytic cleavage of C5 by C5-convertase. Intriguingly, basal neurogenesis is decreased both in C3(-/-) mice and in mice lacking C3aR or mice treated with a C3aR antagonist. The C3(-/-) mice had impaired ischemia-induced neurogenesis both in the subventricular zone, the main source of neural progenitor cells in adult brain, and in the ischemic region, despite normal proliferative response and larger infarct volumes. Thus, in the adult mammalian CNS, complement activation products promote both basal and ischemia-induced neurogenesis.

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Available from: Marcela Pekna, Oct 05, 2015
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    • "With regard to the role of anaphylatoxins in neurogenesis, the receptors for C3a and C5a (C3aR and C5aR, resp.) are expressed on neural progenitor cells and immature neurons [112]. Mice treated with a nonspecific C3aR antagonist (SB290157) displayed decreased formation of new neurons in areas of adult neurogenesis [112]. Altogether, the above results strongly indicate a continuous necessity for the active complement pathway in the normal maintenance of the neurosensory retina and robustly support the notion that disturbances in the physiological activation of CS may have detrimental effects for retinal biology. "
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    ABSTRACT: Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly, especially in Western countries. Although the prevalence, risk factors, and clinical course of the disease are well described, its pathogenesis is not entirely elucidated. AMD is associated with a variety of biochemical abnormalities, including complement components deposition in the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex. Although the complement system (CS) is increasingly recognized as mediating important roles in retinal biology, its particular role in AMD pathogenesis has not been precisely defined. Unrestricted activation of the CS following injury may directly damage retinal tissue and recruit immune cells to the vicinity of active complement cascades, therefore detrimentally causing bystander damage to surrounding cells and tissues. On the other hand, recent evidence supports the notion that an active complement pathway is a necessity for the normal maintenance of the neurosensory retina. In this scenario, complement activation appears to have beneficial effect as it promotes cell survival and tissue remodeling by facilitating the rapid removal of dying cells and resulting cellular debris, thus demonstrating anti-inflammatory and neuroprotective activities. In this review, we discuss both the beneficial and detrimental roles of CS in degenerative retina, focusing on the diverse aspects of CS functions that may promote or inhibit macular disease.
    Research Journal of Immunology 09/2014; 2014:483960. DOI:10.1155/2014/483960
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    • "IL-6, LIF Nakanishi et al. (2007) Increased TNF signaling Hvilsted Nielsen et al. (2011), Mantovani et al. (2011) NAA (Clearance of myelin debris) Kobayashi et al. (2002), Wright et al. (2009) Neuronal plasticity C3 Leon et al. (1994), Li et al. (2010), C1q Hauben et al. (2003), Stevens et al. (2007) BDNF, NGF, NT-4 Yin et al. (2006), Mantovani et al. (2011) NGF, BDNF, NT-3 Kobayashi et al. (2002), Hao et al. (2010), IFN-c Serotonin, NGF Leon et al. (1994), Hammarberg et al. (2000) NT-3 Hauben et al. (2003), Ishii et al. (2012) Oncomodulin Yin et al. (2006) BDNF Coull et al. (2005), Kobayashi et al. (2002) IFN-c Rahpeymai et al. (2006), Hao et al. (2010), BDNF, NT-3 Hammarberg et al. (2000), Shinjyo et al. (2009) Sema4A, NT-3 Be´nard et al. (2008), Ishii et al. (2012) NAA (modulation of H 2 O 2 -induced apoptosis) Warrington et al. (2004), Mantovani et al. (2011) Angiogenesis C5 Norrby (2002), Langer et al. (2010) VEGF Scapini et al. (2004), Ribatti et al. (2011), MMP-9 Justicia et al. (2003), Riboldi et al. (2005) PDGF, TNF-a and VEGF Horiuchi and Weller (1997) VEGF, TNF-a and b, FGF, MMP Norrby (2002) tryptase and chymase Ribatti et al. (2011) VEGF Riboldi et al. (2005), TNF-a, trans-differentiation in ELCs Fernandez Pujol et al. (2001), trogocytosis of VEGF receptor Bourbie´- Vaudaine et al. (2006) Galectin-3 Walther et al. (2000) VEGF Solerte et al. (2005) Neurogenesis C3 Mikami et al. (2004), Rahpeymai et al. (2006), Shinjyo et al. (2009), C5 Be´nard et al. (2008), Popa et al. (2010) BDNF, NGF, NT-4 Schwartz and Shechter (2010), Mantovani et al. (2011) EDN, TNF-a, IFN-c Serotonin, NGF NT-3 Mikami et al. (2004), Ziv and Schwartz (2008) IGF-1 Thored et al. (2007), Huehnchen et al. (2011) RAE1-NKG2D interaction Langer et al. (2010), Popa et al. (2010) IL-4, IGF-1 Scapini et al. (2004), Schwartz and Shechter (2010) BDNF Justicia et al. (2003) SHH, NeuroD6, Ngn-1, Ngn-2 Horiuchi and Weller (1997), Huehnchen et al. (2011) Abbreviations: NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; ROS, radical oxygen species; IL, interleukin; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; NT, neurotrophin; MMP, matrix metalloprotease; MPO, myeloperoxidase, VEGF, vascular endothelial growth factor; TGF, transforming growth factor; PDGF, platelet-derived growth factor; TNF, tumor necrosis factor; LIF, leukemia inhibitory factor; EDN, eosinophilderived neurotoxin; IFN, interferon; mMCP, mouse mast cell protease; FGFs, fibroblast growth factors; ELCs, endothelial-like cells; IGF, insulin-like growth factor, RAE, ribonucleic acid export; Sema4a, semaphorin-4A; SHH, sonic hedgehog homolog; NGN, neurogenin; NAA, natural autoantibodies; H 2 O 2 , hydrogen peroxide. "
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    ABSTRACT: Acute brain injuries cause rapid cell death that activates bidirectional crosstalks between the injured brain and the immune system. In the acute phase, the damaged central nervous system (CNS) activates resident and circulating immune cells via the local and systemic release of soluble mediators. This early immune activation is necessary to confine the injured tissue and foster the clearance of cellular debris, which would ultimately bring the inflammatory reaction to a close. In the chronic phase, a sustained immune activation is described in many CNS disorders, and the degree of this prolonged response has variable effects on the spontaneous brain regenerative processes. The challenge for treating acute CNS damages is to understand how to optimally engage and modify these immune responses, thus providing new strategies that will compensate for tissue lost to injury. Here we have reviewed the available information about the role and function of the innate and adaptive immune responses in influencing CNS plasticity during the acute and chronic phases of recovery after injury. We have examined how CNS damage evolves along the activation of main cellular and molecular pathways that ultimately are associated to intrinsic repair, neuronal functional plasticity and facilitation of tissue reorganization.
    Neuroscience 04/2014; 283. DOI:10.1016/j.neuroscience.2014.04.036 · 3.36 Impact Factor
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    • "These results coupled with published findings about the effect of C3a on stem cells (17, 67) suggest a new realization as to the dominant biological role of this anaphylatoxin: Historically C3a and C5a have been discussed together as proinflammatory mediators, and whereas this is certainly correct for C5a, studies dealing with stem cells suggest that the true biological role of C3a may not be that of an inflammatory mediator but rather a local wound healing factor. The effect of C3a to potentiate bone marrow retention of hematopoietic stem cells [64], its neuroprotective effect on neural progenitors [62], the ability of C3a to chemo-attract MSC [17] and the findings presented here all point to a reparative function for this activation peptide derived from complement C3. "
    Journal of biomedical science and engineering 01/2013; 6(08):1-13. DOI:10.4236/jbise.2013.68A1001 · 0.27 Impact Factor
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