Page 140 - Read Online

involved in neuronal maintenance, injury, and repair that neurons in the brain are vulnerable to excess
in a manner similar to peripheral macrophages. [23] ROS and RNS. Oxidative stress could result in the
Microglial cells are a predominant source of various death of newly-born neurons by disrupting signaling
inflammatory cytokines, that is, interleukin-1 beta processes, dysfunction of ion homeostasis, and protein
(IL-1β), tumor necrosis factor-alpha (TNF-a), and misfolding. [29]
interferon-gamma (IFN-γ), which can then induce
a broad spectrum of inflammatory reactions. The The signaling pathways involved in lead-induced
activation of microglia and astrocytes in response microglial activation, however, need more investigation.
to internal and external stimuli or insults might In response to various environmental toxins including
further increase the release of cytotoxic substances, lead, microglia could enter the activated state and
pro-inflammatory cytokines, ROS, and excitatory release ROS. [31] Pattern recognition receptors expressed
amino acids, thus causing further neuronal injury in on microglia might be one common signaling pathway.
the brain. [22] For example, toll-like receptors act as initiators of the
nuclear factor kappa B (NF-κB) pathway when exposed
Lead‑induced inflammatory cytokines in microglial cells to several toxins, such as lipopolysaccharide (LPS),
Obvious morphological change and higher synthesis resulting in the release of pro-inflammatory cytokines.
[32]
of cytokines have been observed in activated However, it is still not clear how lead could induce
microglial cells after lead exposure. [10,11,24] For microglial activation and trigger inflammatory cytokine
instance, elevated expression of IL-1β and TNF-a production, which remains a critical question to be
is found in the cerebral cortex after lead exposure, answered.
as well as increased expression of IL-1β and IL-6 in
the hippocampus. [25,26] In vitro experiments have also ASTROCYTIC ACTIVATION AND THE
confirmed the elevation of TNF-a expression after NEUROINFLAMMATORY RESPONSE
lead exposure. [27] Gene expression analysis has shown
that levels of the pro-inflammatory factors IL-6 and The neurovascular unit in the brain comprises
TNF-a are significantly perturbed by the lead insult of neurons, blood vessels and their adjacent
in multiple brain regions. [19,20] These cytokines are astrocytes. [33,34] The concept of a functional unit is a
co-expressed in glial cells in response to lead crossing new one, and emphasizes the interaction between
the blood-brain barrier (BBB) and might also represent neurons and astrocytes under both normal and
a mechanism for lead toxicity to the immature brain. pathological physiological conditions. Astrocytes play
Conversely, anti-inflammatory factors such as IL-10 and a critical role in neuron function, including energy
transforming growth factor beta (TGF-β) are decreased support, metabolism, and synapse formation. [35,36]
in the cortex in response to lead, as detected by real Astrocytes maintain the trans-endothelial electric
time-polymerase chain reaction. resistance (TEER) of the BBB. [37] Under pathological
conditions, astrocytes might remove toxic substances
Lead‑induced reactive oxygen species generation in and balance electrolyte and water levels. [33] It has been
microglial cells found that lead interferes with astrocyte functions such
Lead exposure might destroy the glial support of as energy metabolism, immune response, and ROS
neuronal cells by increasing ROS and other toxins removal. Furthermore, astrocytes could collaborate with
in microglial cells. [28] The microglial inflammatory microglia to switch on neuroinflammatory reactions in
response is also associated with the production of ROS the brain, and each of these effects can result in BBB
and nitric oxide (NO)-dependent reactive nitrogen dysfunction and injury to neurons.
species (RNS). [19] Nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase (NOX), which is Lead exposure leads to the insufficient supply of
ubiquitously expressed in microglia, contributes much energy from astrocytes to neurons. Astrocytes contain
to the production of superoxide and the induction a large number of mitochondria for energy and
of ROS. [29] Furthermore, NOX could be activated in glutamate metabolism. Neurons in the brain show
monocytes and microglial cells by IL-1β, TNF-a, IFN-γ, a preference for lactose and glutamine provided by
[19]
and other pro-inflammatory cytokines. The inducible astrocytes via shuttle routes. [38] Glycogen is exclusively
NO synthase (iNOS) is also prevalent in microglia, and localized in astrocytes in the adult brain [39] and can
microglial NO generation regulates vascular relaxation be metabolized to pyruvate, which is converted to
and initiates rapidly induced, transiently regulated lactate by lactate dehydrogenase mainly in astrocytes
signaling events. [30] On the other hand, lead also and then transported to neurons. When energy is
increases NOX, which causes superoxide production insufficient, astrocytes can also use glycolysis from
and inhibits antioxidant production, and increases the stored glycogen for the use of neurons. [40,41] Glycogen
accumulation of ROS in the brain. [22] It is well-known metabolism in astrocytes is also required for long-term

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