The complement system is an integrated part of the natural innate immune response in the brain

Abstract

ABSTRACT The complement system consists of a group of proteins that play essential roles in coordinating the host defense to infection. It can be activated by two primary pathways, namely the classical and the alternative. This study aimed to determine the cellular distribution and the regulation of the genes encoding the proteins that are essential in guiding these pathways in the central nervous system (CNS) during innate immune recognition in mice. The results show a low‐to‐moderate C3 mRNA signal in few nonneuronal structures under basal conditions, whereas a robust C5 expression level was found in numerous populations of neuronal and nonneuronal cells. However, hybridization signal for the gene encoding the anaphylatoxin C5a receptor (C5aR) was low in the brain of vehicle‐administered mice. The constitutive C5 mRNA levels remained unaltered during endotoxemia, but a strong and transient de novo expression of the other members of the complement protein family was found in the brain of mice that received a single systemic bolus of lipopolysaccharide (LPS). Indeed, transcriptional activation C3 and factor B genes occurred in the circumventricular organs and a wave of C3aR‐expressing cells took place from the regions devoid of blood‐brain barrier to deeper brain parenchyma. The C5aR mRNA levels also increased in the cerebral endothelium at 1 h post‐LPS challenge, and the signal became gradually positive in microglial cells surrounding the capillaries and thereafter across the brain parenchyma. The present data provide evidence of an elegant pattern of expression and de novo transcription of key members of the complement system in the CNS, which underlies a sophisticated innate immune system that is triggered by circulating cell wall components of gram‐negative bacteria.