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memory formation in the brain. Lead exposure causes glial fibrillary acidic protein (GFAP). [49,50] Therefore,
[42]
morphological and functional changes in astrocytic the response to lead in astrocytes may affect the BBB.
mitochondria. Creatine kinase and pyruvate kinase It has been shown that lead in the brain accumulates
[9]
are two key enzymes in astrocytes that are involved in predominantly in astrocytes, as opposed to neurons. [51,52]
the production of pyruvate and lactate, and lead can Another culture experiment has shown that younger
bind to their sulfhydryl groups and decrease activity, astrocytes accumulate and retain more lead than older
resulting in an insufficient supply of pyruvate and astrocytes. To protect neurons against lead, astrocytes
[53]
lactate from astrocytes to neurons. [16] Lead can also act serve as a lead pool in the process of neurogenesis.
on cytochrome C and adenosine triphosphate synthase However, because astrocytes are not able to remove lead
to cause dysfunction of the electron transport chain from their own cytoplasm effectively, the accumulated
in mitochondria and generation of free radicals. [14,43] lead will finally cause progressive damage of astrocytes,
Mitochondrial dysfunction in astrocytes affects the the BBB, and nearby neurons.
survival of motor neurons. [44] Accumulation of free
radicals and ROS might enhance the lack of energy and The response of microglia and astrocytes to
glutamine, eventually causing neuronal apoptosis. [15] neuroinflammation
Liu et al. has proposed that activation of microglia in
[18]
Lead triggers inflammation through a collaboration response to pathological conditions such as trauma, stroke,
of astrocytes with microglia. The functional or neurodegenerative disorders occurs before activation
collaboration between astrocytes and microglia might of astrocytes. For instance, the activation of astrocytes
play an important role in neuroinflammation and occurs subsequently to microglial activation in respect
BBB dysfunction in the brain. [45] Overexpression of to the cytokine expression sequence in Alzheimer’s
inflammatory stimuli in the neurovascular unit may disease. [54,55] A study with trimethyltin (TMT) treated rats,
start a response to clear antigenic material, leading to a model of neurodegenerative disease, revealed that GFAP
destruction of the BBB as well as neuronal damage. significantly increases following microglial activation and
Following lead exposure, astrocytes secrete a number that microglial activation requires lower concentrations
of inflammatory cytokines such as TNF-a, IL-6, and of TMT than activation of astrocytes. [56] Considering
IL-10 into surrounding tissues. [45] These cytokines that astrocytes are closer to the peripheral environment
further mediate the immune response, including anatomically and more easily store toxic substances like
activation of microglia and macrophages, and induce lead, it may also be an imperceptible inflammatory signal
other adverse reactions, which might eventually result released from astrocytes such as low amounts of TNF-a,
in the destruction of BBB tight junctions. Matrix free radicals, or ROS/NO that further initiates activation
metalloproteinases (MMPs) are an important family of microglial cells, leading to an inflammatory response.
of proteins composed of a variety of zinc-dependent
enzymes that are capable of degrading extracellular The role of inflammatory cytokines and receptors in
matrix proteins such as collagen, gelatin, viscous microglial‑astrocytic interactions
protein, fibronectin, and proteoglycans. [46] It has been Reciprocal activation of microglia and astrocytes mainly
[57]
hypothesized that inflammatory cytokines induce depends on inflammatory cytokines or their receptors.
production of MMP-2 and MMP-9, two proteinases Previous studies have shown that cytokines secreted
that degrade the extracellular matrix and basement from activated microglia also promote activation
membrane, in astrocytes, resulting in increased of astrocytes. Among those cytokines, IL-1 is a key
permeability of the BBB. [47] Other studies have mediator. IL-1β, mainly from microglia, can be rapidly
shown that low concentrations of pro-inflammatory expressed and may work to increase the secretion other
cytokines (such as TNF-a or IL-1β) or lead did not cytokines such as IL-6, mainly from astrocytes, in order
influence MMP-9 expression when administered to promote inflammation. [35] Moreover, IL-1 might
separately, but combined administration of lead and decrease the ability of astrocytes to reabsorb glutamic
cytokines could induce a marked synergistic elevation acid and promote the release of free radicals. [58,59]
in MMP-9 expression. [48] Experiments have shown that IL-1 receptor antagonists
prevent pathological damage to astrocytes, indicating
[60]
FUNCTIONAL CROSSTALK BETWEEN MICROGLIA that microglia might indirectly affect the function
AND ASTROCYTES IN NEUROINFLAMMATION of astrocytes. In addition, microglial activation also
promotes astrocytes to secrete TGF-β1 and IL-10. [61]
The start of an inflammatory reaction to lead exposure When the severity of the immune response reaches
depends on the interaction between the inflammatory a certain extent, however, TGF-β initiates a feedback
responses of astrocytes and microglial cells. Following loop to reduce the level of IL-1, inhibiting microglial
lead exposure, activation of astrocytes surrounding activation and resulting in suppression of inflammation
blood vessels is indicated by increased expression of in the CNS. [62]

132 Neuroimmunol Neuroinflammation | Volume 2 | Issue 3 | July 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 3 | July 15, 2015 133