TNF-ALPHA-MEDIATED EXPRESSION OF THE RECEPTOR FOR ANAPHYLATOXIN-C5A ON NEURONS IN EXPERIMENTAL LISTERIA MENINGOENCEPHALITIS

The anaphylatoxin C5a has been implicated in the pathogenesis of bacte rial meningitis as a potent mediator of inflammation in the subarachno id space. We investigated the expression of the receptor for C5a (C5aR ) in brains of mice with experimental Listeria monocytogenes (LM) meni ngoencephatitis. In the course of the disease, infiltrating cells in t he meninges and the ventricles were found to express C5aR mRNA and pro tein. In the brain parenchyma, very low constitutive C5aR expression w as seen on pyramidal neurons and Purkinje cells. However, in LM-infect ed mice, a dramatic increase in C5aR expression occurred on neurons st arting 6 h after infection and was maximal between 24 and 36 h. TNF-al pha was identified as an essential mediator of neuronal C5aR expressio n, since mice lacking the genes for TNF and Iymphotoxin-alpha (TNF/lym photoxin-alpha -/- mice) showed significantly attenuated C5aR expressi on after LM infection. Furthermore, i.p. injection of recombinant TNF- alpha induced enhanced C5aR expression in the brains of TNF/lymphotoxi n-alpha -/- mice and in normal animals even in the absence of a bacter ial infection. We also assessed the levels of anaphylatoxin C5a in the cerebrospinal fluid of patients with infectious meningitis. C5a was d etected in all patients with bacterial meningitis (n = 9), in 6 of 18 patients with aseptic meningitis, and in 1 of 66 control patients. The finding of TNF-alpha-mediated C5aR expression on neurons in experimen tal Listeria meningitis and the detection of the ligand, C5a, in the c erebrospinal fluid of human patients with infectious meningitis presen t new directions in the investigation of the pathophysiologic sequelae leading to secondary brain damage.