Inflammatory Pathways in Spinal Cord Injury - International Review of Neurobiology - page 133

interest, as injury and disease often elicit stress-related and inflammatory
stimuli that can activate the p38 mitogen-activated protein kinase (MAPK).
However, studies inhibiting p38 MAPK after SCI have shown differing re-
sults, from slightly improved outcome (i.e., increased standing frequency)
and reduced apoptosis ( Horiuchi, Ogata, Morino, Chuai, & Yamamoto,
2003; Xu, Wang, et al., 2006 ) to no improvements in locomotor
recovery ( Stirling, Liu, Plunet, Steeves, & Tetzlaff, 2008 ). The inhibitors
used to block p38 MAPK, however, block both its beneficial and
detrimental effects, which may account for these results. One of the genes
further downstream in the p38 MAPK pathway, and so likely to have
more selective biological effects, is MK2. MK2 is activated by
phosphorylation ( Gaestel, 2006 ), which results in the increased production
and activation of matrix metalloproteinases (MMPs) ( Xu, Chen, &
Bergan, 2006 ), proinflammatory cytokines ( Kotlyarov et al., 1999;
Winzen et al., 1999 ), and nitric oxide ( Thuraisingam et al., 2007 ), factors
that have been shown to have detrimental effects after SCI. Moreover,
studies using MK2 knockout mice have shown reduced neurotoxicity
and neuroinflammation in models of Parkinson's disease ( Gomez-Nicola,
Valle-Argos, Pita-Thomas, & Nieto-Sampedro, 2008 ) and cerebral ischemia
( Wang et al., 2002 ). MK2 can modulate inflammation via binding to
AU-rich elements in the 3 0 untranslated region of cytokine mRNAs such as
TNF- a , and help stabilize mRNA transcripts allowing for efficient
translation of proinflammatory cytokines ( Mahtani et al., 2001; Neininger
et al., 2002; Winzen et al., 1999 ). It can also phosphorylate tristetraprolin
( Chrestensen et al., 2004; Mahtani et al., 2001 ) and Hsp27, and the former
can also affect cytokine production ( Hitti et al., 2006 ).
We observed that the phosphorylated, active form of MK2 (pMK2)
reaches peak expression at 7 days after spinal cord contusion injury in mice,
and is expressed in microglia/macrophages, astrocytes, and some neurons
( Fig. 5.1 ). At 12 h after injury, over 60% of GFAP þ astrocytes at the lesion
site express pMK2 suggesting that astrocytes at this early phase may contrib-
ute to cytotoxic effects possibly via expression of proinflammatory cytokines
such as TNF- a ( Pineau & Lacroix, 2007 ). By 7 days after SCI when only
10% of astrocytes express MK2, the astroglial scar may have a beneficial
effect by limiting the infiltration of immune cells into the spinal cord
( Karimi-Abdolrezaee & Billakanti, 2012 ). Interestingly, we found a signif-
icant improvement in locomotor recovery in MK2 / mice as compared to
wild-type littermates after a moderate contusion injury, starting 5 days after
injury until the end of the study at day 28. Using the Basso Mouse Scale