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Turner et al. LPS preconditioning neuroprotective

FJB staining has been associated with motor deficits microglial changes. LPS can promote the infiltration
following TBI. [32] In a future study, we plan to look at of macrophages into the brain, which helps resolve
the role of LPS preconditioning in preventing motor the microglia response after diffuse traumatic
deficits following TBI. axonal injury. [35] Microglia is broadly grouped into
pro-inflammatory M1 microglia and pro-survival
Reactive astrocytes can inhibit axonal regrowth anti-inflammatory M2 microglia. [36] The balance of
after an axon is severed. [33] OSM activity increases M1 to M2 microglia is tightly controlled following
in demyelinated areas, leading to an upregulation injury. [37] M1 microglia can exacerbate axonal injury,
of OSMR. This upregulation indicates a loss thereby limiting functional recovery. We showed
of detrimental connectivity, [22] while decreased that LPS preconditioning selectively inhibited
OSMR indicates preservation of myelin integrity the M1 response. LPS caused an acute increase
and axonal tracts. Our findings show that LPS in pro-inflammatory markers, which may signal
preconditioning significantly reduces OSMR levels peripheral macrophages to cross brain vasculature
[Figure 7]. Interestingly, GFAP expression was also by chemotaxis. Peripheral macrophages alter the
downregulated, which may reflect an interaction inflammatory mileu of the brain while attenuating
between LPS and toll like receptor 4 (TLR4). Low- microglial activity. [38] In contrast, M2 microglia
dose LPS administration can stimulate TLR4, are largely unaffected due to the earlier peak of
which activates signaling cascades to suppress activation after injury, which we have shown using
innate immunity and astrocyte activation. These non-differentiated IBA-1 imaging. [39] The brain
cell-signaling events permit axonal regeneration establishes functional recovery by shifting the
without the threat of glial scar formation. [34] As long balance away from M1 microglia.
as myelin integrity is maintained, neurons can
re-innervate most of their lost connections. The LPS has been associated with inflammation.
clinical use of LPS preconditioning is obviously Suppressing inflammation limits the effect of LPS on
limited because injury cannot be predicted, but human physiology. [40] LPS increases tissue necrosis
targeting TLR4 pharmacologically might represent factor α, interleukin 6, and interleukin 1 expression
a reasonable strategy. Further work is needed to [Figure 6]. [41] LPS preconditioning reduces neuronal
determine the exact interactions between low-dose loss and microglia activation in other injury models,
LPS administration and TLR4. such as global hypoxia. [42] In the present study, LPS
preconditioning also significantly reduced neuronal
In addition to effects on astrocytosis, LPS degeneration following diffuse axonal injury.
preconditioning has also been associated with Chronic LPS-mediated inflammation is detrimental

Figure 7: Hypothetical schematic showing the mechanism of LPS action. LPS: lipopolysaccharide; TBI: traumatic brain injuries; OSMR:
oncostatin M receptor; TLR4: toll like receptor 4
Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ January 20, 2017 13