Neuronal Expression of a Functional Receptor for the C5a Complement Activation Fragment

Abstract

The present studies were undertaken to determine whether neuronal subsets in normal brains constitutively express functionally competent C5a receptors. In situ hybridization studies coupled with immunohistochemical approaches revealed that most neurons in the hippocampal formation, many pyramidal cortical neurons, and cerebellar Purkinje neurons in normal human and murine brains constitutively express C5a receptors. Neuronal C5a receptors bound C5a-coated fluorescent microspheres, and primary rodent hippocampal neurons responded to C5a with increased calcium fluxes via a pertussis-sensitive, presumably Gi-coupled protein. Additional studies with human neuroblastoma cells conducted to address the functional role of C5a receptors revealed that C5a triggered rapid activation of protein kinase C and activation and nuclear translocation of the NF-κB transcription factor. In addition, C5a was found to be mitogenic for undifferentiated human neuroblastoma cells, a novel action for the C5aR. In contrast, C5a protected terminally differentiated human neuroblastoma cells from toxicity mediated by the amyloid Aβ peptide. Thus, normal rodent hippocampal neurons as well as undifferentiated and differentiated human neuroblastoma cells express functional C5a receptors. These results have implications for understanding the role of neuronal C5aR receptors in normal neuronal development, neuronal homeostasis, and neuroinflammatory conditions such as Alzheimer’s disease.

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

“…In situ hybridization and immunohistochemistry analysis also revealed a constitutive expression of mouse and rat C3aR in cortical and hippocampal neurons (17,19) as well as in cerebellar Purkinje cells (19). Controversial results have been published for C5aR, which was first hardly detected by in situ hybridization or immunohistochemistry in neurons from rodent adult brains (18,22) but was recently identified on mouse pyramidal neurons in hippocampus and neocortex as well as on Purkinje cells in cerebellum (26). C5aR expression seemed induced by inflammatory stimuli (18,22) and is found in cultured murine corticohippocampal neurons (21,28) and neuroblastoma cells (24 -26).…”

“…Recently, it has been reported that C5a mediates apoptosis in neuroblastoma cells (24,25). In contrast, C5a protects differentiated human neuroblastoma cells from the neurotoxic effect of the amyloid A␤ peptide (26), and a possible neuroprotective role for C5a has been suggested in Alzheimer's disease (27). Moreover, C5-deficient mice are more sensitive to kainic acid excitotoxicity (28), and C5a has been found to protect neurons from apoptotic cell death in vitro and in vivo in a model of intracerebroventricular kainic injection in mice (21).…”

Cancer and the Complement Cascade

“…In the search for evidence of C5aR in neurons, researchers discovered that C5a promotes proliferation of undifferentiated human neuroblastoma cells (44). The proliferative effects of C5a/C5aR binding seem to be partially mediated by protein kinase C and NF-κB activation (44). Complement-mediated tumor proliferation has also been observed in the TC-1 syngeneic model of murine cervical cancer (11).…”

“…Intriguingly, two studies have shown direct complementmediated neoplastic proliferation. In the search for evidence of C5aR in neurons, researchers discovered that C5a promotes proliferation of undifferentiated human neuroblastoma cells (44). The proliferative effects of C5a/C5aR binding seem to be partially mediated by protein kinase C and NF-κB activation (44).…”

The Chemoattractant Receptor-like Protein C5L2 Binds the C3a des-Arg77/Acylation-stimulating Protein

“…Although initially described as leukocyte chemoattractants and anaphylatoxins, it is now clear that C5a and C3a are involved in microbial host defense, immune regulation (1), and protection against toxic insult (2)(3)(4)(5). C5a and C3a are also reported to have psychopharmacological effects on feeding and drinking behavior (6,7).…”