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also increases between 1 and 3 h after ischemia but its biphasic behavior is
faster (24-36 h) than that seen after SCI (
Denes, Thornton, Rothwell, &
Allan, 2010; Wang, Tang, & Yenari, 2007
). The first responders after SCI to
express cytokines that initiate the immune response to injury are therefore the
resident CNS cells including microglia, astrocytes, neurons, oligodendrocytes,
and endothelial cells.
It is also instructive to know the time course of the entry of different
peripheral immune cell populations, and the activation of endogenous
microglia to understand when and how to modulate these responses to reduce
secondary damage and promote recovery. As mentioned above, resident
microglia are the first immune cell population to respond to injury within
minutes. Neutrophils are the first peripheral immune cell type to enter the
injured spinal cord. They enter the cord within hours, reach a peak at 24 h
and are markedly reduced by 3 days in rodents (
Donnelly & Popovich,
2008; Yang et al., 2005
) and humans (
Fleming et al., 2006; Norenberg,
Smith, & Marcillo, 2004
). This differs from brain ischemia/reperfusion in
which the first cells to enter the injured brain are macrophages starting at
12 h and peaking at 72 h, while neutrophils enter the brain only 72 h after
the reperfusion and stay longer for 7 days (
Gelderblom et al., 2009
). By
fluorescence-activated cell sorting (FACS) analysis, neutrophils comprise
over 90% of the cellular infiltrates at 12 h after SCI (
Stirling & Yong, 2008
).
Monocytes andmacrophages from the peripheral circulation enter the spinal
cord at around 3-4 days (
Pineau, Sun, Bastien, & Lacroix, 2010
). Peripheral
macrophages become rapidly activated and along with activated microglia begin
to phagocytose tissue debris. When they become activated and have phagocy-
tosed cellular material, macrophages derived from the periphery cannot be dis-
tinguished frommicroglia based on their morphology or antigenic profile. They
are therefore referred to as microglia/macrophages. Quantification by FACS
analysis shows that microglia/macrophages constitute over 70% of the
CD45
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population at 4 days after SCI in mice (
Stirling & Yong, 2008
). These
cells reach peak numbers by 7-10 days after contusion injury in rodents and re-
main in the tissue for several weeks to months (reviewed by
Donnelly &
Popovich, 2008
). The presence of and changes in the numbers of T and B lym-
phocytes after SCI vary in mice, rats, and humans (
Fleming et al., 2006; Kigerl,
McGaughy, & Popovich, 2006; Sroga, Jones, Kigerl, McGaughy, & Popovich,
2003
). In C57BL/6 mice, they are found as early as 1 week after SCI, reaching
their peak at 42 days, and contribute at the later stages to CNS pathology
(
Ankeny, Lucin, Sanders, McGaughy, & Popovich, 2006; Ankeny &
Popovich, 2009; Sroga et al., 2003
). In contrast, in the injured human spinal
