Biology Reference
In-Depth Information
about whether microglia/macrophages are good or bad after SCI, recent
evidence from the broader literature suggests that these differences are likely
to be due to differences in polarization states (
David & Kroner, 2011
).
Macrophages polarized to an M1 state are proinflammatory and cytotoxic
while M2-polarized macrophages are anti-inflammatory and protective. See
review by David and Kroner (2011) for further discussion on macrophage
activation and polarizing signals. Interestingly, recent work has shown that
the environment of the injured spinal cord favors polarization to a
proinflammatory M1 state (
Kigerl et al., 2009
).
4. IDENTIFICATION OF NOVEL TARGETS THAT MEDIATE
INFLAMMATORY RESPONSES AFTER SCI
Several studies done over the past decade have led to the identification
of molecular targets that modulate inflammation after SCI. These include
proinflammatory cytokines such as TNF-
a
and IL-1
b
(
Genovese et al.,
2008; Zong, Zeng, Wei, Xiong, & Zhao, 2012
), integrins such as
a
D
b
2
and
a
4
b
1
involved in the migration of immune cells into the injured cord
(
Fleming, Bao, Cepinskas, & Weaver, 2010; Gris et al., 2004
), free
radical generation (
Bao et al., 2004, 2008
), and others. We have recently
reported on the identification of several novel inflammatory mediators
that play a role in SCI. As inflammation in SCI is a complex process
involving a number of cellular and molecular pathways, we used different
strategies to identify novel molecular targets. (i) One approach was to
carry out an Affymetrix gene array screen of spinal cord tissue taken at
the peak period of the macrophage response to identify genes of interest,
which led to the identification of MAPK-activated protein kinase 2
(MK2). (ii) Another approach was to look at other models of CNS injury
to identify potential mediators of secondary damage. This led to studies
on
KCNN4
/KCa3.1, an intermediate conductance Ca
2
รพ
-activated
potassium channel which we found is expressed by astrocytes and may
mediate secondary damage after SCI. (iii) As part of the inflammatory
response in SCI deals with wound healing, we looked at wound healing
in the skin. This led to studies on secretory leukocyte protease inhibitor
(SLPI), a serine protease inhibitor produced by neutrophils and
macrophages that has both anti-inflammatory and wound-healing
properties. (iv) We also identified several lipolytic enzymes belonging to
the PLA
2
superfamily that generate metabolites that give rise to a wide
