Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury

Abstract

The inflammatory response contributes importantly to secondary tissue damage and functional deficits after spinal cord injury (SCI). In this work, we identified mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of p38 MAPK, as a potential target using microarray analysis of contused spinal cord tissue taken at the peak of the inflammatory response. There was increased expression and phosphorylation of MK2 after SCI, with phospho-MK2 expressed in microglia/ macrophages, neurons and astrocytes. We examined the role of MK2 in spinal cord contusion injury using MK2 Ϫ/Ϫ mice. These results show that locomotor recovery was significantly improved in MK2 Ϫ/Ϫ mice, compared with wild-type controls. MK2 Ϫ/Ϫ mice showed reduced neuron and myelin loss, and increased sparing of serotonergic fibers in the ventral horn caudal to the injury site. We also found differential expression of matrix metalloproteinase-2 and 9 in MK2 Ϫ/Ϫ and wild-type mice after SCI. Significant reduction was also seen in the expression of proinflammatory cytokines and protein nitrosylation in the injured spinal cord of MK2 Ϫ/Ϫ mice. Our previous work has shown that macrophages lacking MK2 have an anti-inflammatory phenotype. We now show that there is no difference in the number of macrophages in the injured spinal cord between the two mouse strains and little if any difference in their phagocytic capacity, suggesting that macrophages lacking MK2 have a beneficial phenotype. These findings suggest that a lack of MK2 can reduce tissue damage after SCI and improve locomotor recovery. MK2 may therefore be a useful target to treat acute SCI.

Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 in Neuroinflammation, Heat Shock Protein 27 Phosphorylation, and Cell Cycle: Role and Targeting

“…Microarray analysis of spinal cord tissues taken at the peak of the inflammatory response to spinal cord injury showed an increased expression of phosphorylated MK2 in microglia and also in neurons and astrocytes. Locomotor recovery was significantly improved in MK2-deficient animals and was associated with reduced neuronal and myelin loss, and decreased expression of proinflammatory cytokines and decreased protein nitrosylation (Ghasemlou et al, 2010).…”

“…Thus, MK2 emerged as a potential anti-inflammatory target, as convincingly documented by the increasing number of publications and reviews related to MK2 inflammation. In addition, MK2 governs not only peripheral inflammation but also neuroinflammation, the inflammation of the brain (Culbert et al, 2006;Thomas et al, 2008b;Ghasemlou et al, 2010). As the prominent kinase phosphorylating heat shock protein 27 (Hsp27) (Stokoe et al, 1992), MK2 has become a promising target for cancer treatment.…”

Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice

“…Serial spinal cord cross-sections were stained with cresyl violet to measure motor neuron survival over a 2-mm segment of the spinal cord centered on spinal level L4-L5. Criteria used to identify motor neuron profiles were the appearance of Nissl substance, a euchromatic nucleus, and cells with a diameter of at least 12.5 μm, and the ventral horn was defined as the area below (i.e., ventral) a horizontal line drawn at the level of the central canal (72). Motor neurons in the ipsilateral and contralateral ventral horn were counted at 100-μm intervals in the spinal cords of hHsp27 Tg and LM control mice 55 days after SNT/resuture.…”

Epigenetics of Neural Repair Following Spinal Cord Injury

“…Its prototype is the extracellular signal-regulated kinase (ERK)/mitogen-and stress-activated kinase (MSK)/cyclic-adenosine monophosphate regulatory element binding protein (CREB) pathway, where ERK activates its downstream target, MSK, to phosphorylate CREB [76][77][78][79]. This phosphorylation and activation of CREB recruits CREB binding protein, a HAT that regulates local chromatin structure as part of CREB-dependent activation of nuclear gene transcription [80]. Second, the nuclear factor kappa B (NFκB) signaling pathway appears to control histone acetylation and chromatin structure in the CNS by mechanisms that are still being elucidated [81,82].…”