Immune Players in the CNS: The Astrocyte
Introduction:
In
the finely balanced environment of the central nervous system astrocytes, the
most numerous cell type, play a role in regulating almost every physiological
system. First found to regulate extracellular ions and pH, they have since been
shown to regulate neurotransmitter levels, cerebral blood flow and energy
metabolism. There is also growing evidence for an essential role of astrocytes
in central immunity, which is the topic of this review. In the healthy state,
the central nervous system is potently anti-inflammatory but under threat
astrocytes readily respond to pathogens and to both sterile and pathogen
induced
cell
damage. In response, astrocytes take on some of the roles of immune cells,
releasing cyto- and chemokines to influence effector cells, modulating the
blood–brain barrier and forming glial scars. To date,
much of the data supporting a role
for
astrocytes in immunity have been obtained from in vitro systems; however data
from experimental models and clinical samples support the suggestion that
astrocytes perform similar roles in more complex environments.
The
blood brain barrier:
The
innate immune system offers non-specific defence against foreign pathogens. The
first role of astrocytes in innate immunity is their contribution to the blood
brain barrier (BBB). The BBB prevents many large or polar molecules, such as
antibody or complement, passing from the circulation into the brain parenchyma
but at the same time allows access to small or hydrophobic molecules. While the
principle components of the BBB are cerebral capillary endothelial cells,
astrocytes contribute to the glia limitans which separates the perivascular space from the brain, supports
the pericytes and endothelial cells around the capillaries and limits the entry
of immune cells into the brain in the absence of inflammation. During
inflammation, cells from the CNS release a range of pro-inflammatory cytokines,
including interleukin (IL)-6, tumour necrosis factor (TNF)-α and IL-1β. Reactive astrocytes, respond to those signals in a range of
ways including the release of the angiogenic factor VEGF-A which increases BBB
permeability . That effect is combined with the expression of matrix
metalloproteinase, some of which are astrocyte-specific and which break down
the extracellular matrix to facilitate cell migration . Adhesive molecules such
as VCAM-1 are expressed on astrocytes and endothelial cells, allowing T-cell
migration into the CNS parenchyma. The relative permeability of the BBB affects
the passage of hormones, cytokines and chemokines that modulate immune
responses and also the entry of large molecules such as immunoglobulin and
complement.
General functions of astrocytes:
Astrocytes are a heterogeneous population of cells. There have
been several ways to categorise them but currently, the most frequently used
classification is based on morphology, location and the developmental period in
which they are observed. By maturity, two major classifications of astrocytes,
protoplasmic and fibrous astrocytes, are dominant in mammals.
1. Protoplasmic astrocytes are found through the grey matter where
they envelop synapses and contact endothelial cells, usually having five to
eight major branches that extend fine processes uniformly into the surrounding
tissue.
2.
Fibrous astrocytes are
located in the white matter adjacent to axon bundles where they make contact
with the nodes of Ranvier. Fibrous astrocytes have longer, thinner branches
than protoplasmic astrocytes, smaller bodies and fewer organelles and both
astrocyte types make intimate contact with blood vessels.
Astrocytes
perform a range of activities during development and in the mature brain which
contribute to the development and maintenance of a cohesive cognitive system.
Astrocytes
support an inflammatory response:
The
activation of astrocytes by inflammatory signals leads them to express a
cascade of secondary signals that initiate and control the subsequent immune
response (Fig. 1). The consequence may be the
suppression of the immune response as evidenced by experiments in which T-cells
co-cultured with astrocytes acquire characteristics of regulatory T-cells and
have suppressed.
