Complement Receptor 2Is Expressed in Neural Progenitor Cells and Regulates Adult Hippocampal Neurogenesis

Abstract

Injury and inflammation are potent regulators of adult neurogenesis. As the complement system forms a key immune pathway that may also exert critical functions in neural development and neurodegeneration, we asked if complement receptors regulate neurogenesis. We discovered that complement receptor 2 (CR2), classically known as a co-receptor of the B lymphocyte antigen receptor, is expressed in adult neural progenitor cells (NPCs) of the dentate gyrus. Two of its ligands, C3d and interferon-α (IFN-α), inhibited proliferation of wildtype NPCs but not NPCs derived from mice lacking Cr2 (Cr2−/−) indicating functional Cr2 expression. Young and old Cr2−/− mice exhibited prominent increases in basal neurogenesis compared with wildtype littermates, while intracerebral injection of C3d resulted in fewer proliferating neuroblasts in wildtype than in Cr2−/− mice. We conclude that Cr2 regulates hippocampal neurogenesis and propose that increased C3d and IFN-α production associated with brain injury or viral infections may inhibit neurogenesis.

Deficiency of Adult Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome

“…Numerous studies provide evidence that a lack of neurogenesis significantly diminishes plasticity in the adult brain and interferes with learning and memory (reviewed in Koehl & Abrous, 2011;Mongiat & Schinder, 2011). Different mechanisms have been proposed to regulate neurogenesis in the adult brain, including brain injury (Kernie & Parent, 2010;Moriyama et al, 2011), ischemia (Kernie & Parent, 2010;Kreuzberg et al, 2010), and inflammation (Voloboueva et al, 2010). One of the least studied factors that affects neurogenesis are chromosomal aberrations.…”

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

“…However, the effect of infiltrating innate immune cells and humoral components of the innate immune response, for example, neutrophils, macrophages (Mf), and cytokines/ proteins of the complement cascade, on stem cells remains to be elucidated. In particular, expression of complement receptor CR2 by rodent NPC has recently been identified and shown as a regulator of adult neurogenesis (20), and C3a has been shown to modulate ischemia-induced astrocyte survival (21), suggesting that neural and glial cells can interact with components of the complement cascade.…”

Endogenous Natural Complement Inhibitor Regulates Cardiac Development

“…C3a was implicated in neural stem cell migration and regeneration, because neuronal stem cells express C3aR, and their stimulation by C3a promotes neurogenesis after injury (42), as well as retinal neural regeneration (43). Finally, complement receptor 2 is expressed on neural progenitor cells and plays a role in hippocampal neurogenesis (44).…”

“…Furthermore, the majority of CL-K1 is found in the circulation as a heterocomplex with the related molecule collectin-liver 1; this form is termed collectin-L1/K1 hetero-oligomer (CL-LK) (10). MASP-3 is one of three alternative splice products (MASP-1, MASP-3, and MBL-associated protein [MAp] 44) from the human MASP1 gene (11). MASP-1 and MASP-3 are serine proteases, whereas MAp44 is a truncated product retaining only the domains required for association with PRMs.…”