Lack of galectin-3 improves the functional outcome and tissue sparing by modulating inflammatory response after a compressive spinal cord injury

Mostacada, Klauss; Oliveira, Felipe Leite de; Villa‐Verde, Déa Maria Serra; Martínez, Ana Maria Blanco

doi:10.1016/j.expneurol.2015.07.006

Cited by 33 publications

(22 citation statements)

References 47 publications

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“…Thus, their decreased expression may be closely related to the reduction of T cell infiltration in p38α +/- mice. On the other hand, Galectin-3 and TLR2 have been reported to have protective effects on SCI through regulating inflammatory response ( Kigerl et al, 2007 ; Stirling et al, 2014 ; Gensel et al, 2015 ; Mostacada et al, 2015 ). Among the 15 molecules, only SCI-induced Galectin-3 was higher in p38α +/- mice compared with WT mice, suggesting that the increase of Galectin-3 may also contribute to the less infiltrating leucocytes in p38α +/- mice.…”

Section: Resultsmentioning

confidence: 99%

Genetic and Pharmacological Inhibition of p38α Improves Locomotor Recovery after Spinal Cord Injury

et al. 2017

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One of the mitogen-activated protein kinases, p38α plays a crucial role in various inflammatory diseases and apoptosis of various types of cells. In this study, we investigated the pathophysiological roles of p38α in spinal cord injury (SCI), using a mouse model. Lateral hemisection at T9 of the SC was performed in wild type (WT) and p38α+/- mice (p38α-/- showed embryonic lethality). p38α+/- mice showed a better functional recovery from SCI-associated paralyzed hindlimbs compared to WT mice at 7 days post-injury (dpi), which remained until 28 dpi (an end time point of monitoring the behavior). In histopathological analysis at 28 dpi, there was more axonal regeneration with remyelination on the caudal side of the lesion epicenter in p38α+/- mice than in WT mice. At 7 dpi, infiltration of inflammatory cells into the lesion and expression of cytokines in the lesion were reduced in p38α+/- mice compared with WT mice. At the same time point, the number of apoptotic oligodendrocytes in the white matter at the caudal boarder of the lesion of p38α+/- mice was lower than that of WT mice. At 14 dpi, more neural and oligodendrocyte precursor cells in the gray matter and white matter, respectively, were observed around the lesion epicenter of p38α+/- mice compared with the case of WT mice. At the same time point, astrocytic scar formation was less apparent in p38α+/- than in WT mice, while compaction of inflammatory immune cells associated with the wound contraction was more apparent in p38α+/- than in WT mice. Furthermore, we verified the effectiveness of oral administration of SB239063, a p38α inhibitor on the hindlimb locomotor recovery after SCI. These results suggest that p38α deeply contributes to the pathogenesis of SCI and that inhibition of p38α is a beneficial strategy to recovery from SCI.

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Section: Resultsmentioning

confidence: 99%

Genetic and Pharmacological Inhibition of p38α Improves Locomotor Recovery after Spinal Cord Injury

et al. 2017

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“…They are also congruent with the finding that galectin-3 levels are increased in the serum of Alzheimer’s disease patients (Wang et al, 2015). Further support comes from the observations that a lack of galectin-3 facilitates motor function recovery after spinal cord injury (Mostacada et al, 2015), and that galectin-3 contributes to hypoxic-ischemia injury and ischemia-induced neuronal death (Doverhag et al, 2010; Satoh et al, 2011), findings that suggest a role for galectin-3 in negative regulation of neuronal plasticity. However, these latter findings probably reflect the role of galectin-3 in microglia and its interaction with neurons.…”

Section: Discussionmentioning

confidence: 98%

Galectin-3 Negatively Regulates Hippocampus-Dependent Memory Formation through Inhibition of Integrin Signaling and Galectin-3 Phosphorylation

Chen

Lin

et al. 2017

Front. Mol. Neurosci.

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Galectin-3, a member of the galectin protein family, has been found to regulate cell proliferation, inhibit apoptosis and promote inflammatory responses. Galectin-3 is also expressed in the adult rat hippocampus, but its role in learning and memory function is not known. Here, we found that contextual fear-conditioning training, spatial training or injection of NMDA into the rat CA1 area each dramatically decreased the level of endogenous galectin-3 expression. Overexpression of galectin-3 impaired fear memory, whereas galectin-3 knockout (KO) enhanced fear retention, spatial memory and hippocampal long-term potentiation. Galectin-3 was further found to associate with integrin α3, an association that was decreased after fear-conditioning training. Transfection of the rat CA1 area with small interfering RNA against galectin-3 facilitated fear memory and increased phosphorylated focal adhesion kinase (FAK) levels, effects that were blocked by co-transfection of the FAK phosphorylation-defective mutant Flag-FAKY397F. Notably, levels of serine-phosphorylated galectin-3 were decreased by fear conditioning training. In addition, blockade of galectin-3 phosphorylation at Ser-6 facilitated fear memory, whereas constitutive activation of galectin-3 at Ser-6 impaired fear memory. Interestingly galectin-1 plays a role in fear-memory formation similar to that of galectin-3. Collectively, our data provide the first demonstration that galectin-3 is a novel negative regulator of memory formation that exerts its effects through both extracellular and intracellular mechanisms.

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“…Soon after a head or spinal cord injury, the expression of several proteins related to the inflammatory response is upregulated, including the lectin galectin-3 25 26 27 28 29 . The neuroinflammatory response triggered by TBI is believed to be a major determinant of the secondary cell death after brain trauma.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore our previous studies showed that: (i) galectin-3 is involved in the proinflammatory response triggered by α-synuclein in microglial cells 24 , a hallmark of Parkinson’s disease physiopathology, and (ii) mice lacking galectin-3 were more resistant to hippocampal degeneration in a model of global cerebral ischemia that mimics the brain damage caused by cardiac arrest 22 . Regarding the role of galectin-3 under conditions of brain trauma, several studies have demonstrated striking early increases in the expression of galectin-3 in different trauma models including spinal cord injury 25 26 27 and also in experimental models of TBI 28 29 . Interestingly, a recent study performed in 8 weeks post-contusion spinal cord injured mice, found galectin-3 as one of the most upregulated extracellular proteins 30 , suggesting that galectin-3 plays also a role at later stages of the injury.…”

mentioning

confidence: 99%

Galectin-3 released in response to traumatic brain injury acts as an alarmin orchestrating brain immune response and promoting neurodegeneration

Yip

Carrillo-Jiménez

King

et al. 2017

Sci Rep

120

125

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Traumatic brain injury (TBI) is currently a major cause of morbidity and poor quality of life in Western society, with an estimate of 2.5 million people affected per year in Europe, indicating the need for advances in TBI treatment. Within the first 24 h after TBI, several inflammatory response factors become upregulated, including the lectin galectin-3. In this study, using a controlled cortical impact (CCI) model of head injury, we show a large increase in the expression of galectin-3 in microglia and also an increase in the released form of galectin-3 in the cerebrospinal fluid (CSF) 24 h after head injury. We report that galectin-3 can bind to TLR-4, and that administration of a neutralizing antibody against galectin-3 decreases the expression of IL-1β, IL-6, TNFα and NOS2 and promotes neuroprotection in the cortical and hippocampal cell populations after head injury. Long-term analysis demonstrated a significant neuroprotection in the cortical region in the galectin-3 knockout animals in response to TBI. These results suggest that following head trauma, released galectin-3 may act as an alarmin, binding, among other proteins, to TLR-4 and promoting inflammation and neuronal loss. Taking all together, galectin-3 emerges as a clinically relevant target for TBI therapy.

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Lack of galectin-3 improves the functional outcome and tissue sparing by modulating inflammatory response after a compressive spinal cord injury

Cited by 33 publications

References 47 publications

Genetic and Pharmacological Inhibition of p38α Improves Locomotor Recovery after Spinal Cord Injury

Genetic and Pharmacological Inhibition of p38α Improves Locomotor Recovery after Spinal Cord Injury

Galectin-3 Negatively Regulates Hippocampus-Dependent Memory Formation through Inhibition of Integrin Signaling and Galectin-3 Phosphorylation

Galectin-3 released in response to traumatic brain injury acts as an alarmin orchestrating brain immune response and promoting neurodegeneration

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