Denise van Rossum | PubMed Health

PubMed2004

The microglia-activating potential of thrombin: the protease is not involved in the induction of proinflammatory cytokines and chemokines.

The serine protease thrombin is known as a blood coagulation factor. Through limited cleavage of proteinase-activated receptors it can also control growth and functions in various cell types, including neurons, astrocytes, and microglia (brain macrophages). A number of previous studies indicated that thrombin induces the release of proinflammatory cytokines and chemokines from microglial cells, suggesting another important role for the protease beyond hemostasis. In the present report, we provide evidence that this effect is not mediated by any proteolytic or non-proteolytic mechanism involving thrombin proper. Inhibition of the enzymatic thrombin activity did not affect the microglial release response. Instead the cyto-/chemokine-inducing activity solely resided in a high molecular weight protein fraction that could be isolated in trace amounts even from apparently homogenous alpha- and gamma-thrombin preparations. High molecular weight material contained thrombin-derived peptides as revealed by mass spectrometry but was devoid of thrombin-like enzymatic activity. Separated from the high molecular weight fraction by fast protein liquid chromatography, enzymatically intact alpha- and gamma-thrombin failed to trigger any release. Our findings may force a revision of the notion that thrombin itself is a direct proinflammatory release signal for microglia. In addition, they could be relevant for the study of other cellular activities and their assignment to this protease.

Amino Acid Sequence↗

PubMed2004

Microglia.

Microglia--the macrophage equivalent of the CNS--safeguards and supports neuronal functions. Threats to the CNS homeostasis can trigger a rapid transformation of these cells from a normally "resting" into alerted and "activated" states. Microglia primarily serves the tissue defence and protection when participating in mechanisms of innate and adaptive immunity. On the contrary, excessive acute or chronic microglial activation can provoke severe neuronal and glial damage by carrying or fuelling destructive cascades. Several factors and conditions have already been identified that maintain the resting phenotype or organize and control the activation process. Cells are thereby able to recognize a dangerous signal as well as to sense functional disturbance. Microglial activation is also proving a much more variable and adaptive process than previously noticed. Aiming at microglia as a therapeutic target, research may focus on intracellular pathways that are probably common to activation scenarios as triggered by various receptor systems. Certain signalling elements may have key roles in the cytosolic integration of sensory inputs and a conversion into programs of executive performance. As the integrative aspect of microglial activation becomes illuminated hope builds up also on strategies for selective interference with harmful outcomes in favour of the--phylogenetically approved--beneficial potential of these fascinating cells.

Animals↗