C1q, the recognition subcomponent of the classical pathway of complement, drives microglial activation.
Microglia, central nervous system (CNS) resident phagocytic cells, persistently police the integrity of CNS tissue and respond to any kind of damage or pathophysiological changes. These cells sense and rapidly respond to danger and inflammatory signals by changing their cell morphology; by release of cytokines, chemokines, or nitric oxide; and by changing their MHC expression profile. We have shown previously that microglial biosynthesis of the complement subcomponent C1q may serve as a reliable marker of microglial activation ranging from undetectable levels of C1q biosynthesis in resting microglia to abundant C1q expression in activated, nonramified microglia. In this study, we demonstrate that cultured microglial cells respond to extrinsic C1q with a marked intracellular Ca(2+) increase. A shift toward proinflammatory microglial activation is indicated by the release of interleukin-6, tumor necrosis factor-alpha, and nitric oxide and the oxidative burst in rat primary microglial cells, an activation and differentiation process similar to the proinflammatory response of microglia to exposure to lipopolysaccharide. Our findings indicate 1) that extrinsic plasma C1q is involved in the initiation of microglial activation in the course of CNS diseases with blood-brain barrier impairment and 2) that C1q synthesized and released by activated microglia is likely to contribute in an autocrine/paracrine way to maintain and balance microglial activation in the diseased CNS tissue.
Färber
Katrin
K
Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Cheung
Giselle
G
Mitchell
Daniel
D
Wallis
Russell
R
Weihe
Eberhard
E
Schwaeble
Wilhelm
W
Kettenmann
Helmut
H
D000818:Animals; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015922:Complement C1q / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D037601:Mannose-Binding Lectin / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016897:Respiratory Burst / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D037601:Mannose-Binding Lectin; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D015922:Complement C1q; D002118:Calcium