Abstract
BackgroundPleiotrophin (PTN) is a cytokine found highly upregulated in the brain in different disorders characterized by overt neuroinflammation such as neurodegenerative diseases, drug addiction, traumatic injury, and ischemia. In the present work, we have explored whether PTN modulates neuroinflammation and if Toll-like receptor 4 (TLR4), crucial in the initiation of an immune response, is involved.MethodsIn immunohistochemistry assays, we studied lipopolysaccharide (LPS, 7.5 mg/kg i.p.)-induced changes in glial fibrillary acidic protein (GFAP, astrocyte marker) and ionized calcium-binding adaptor molecule 1 (Iba1, microglia marker) expression in the prefrontal cortex (PFC) and striatum of mice with transgenic PTN overexpression in the brain (PTN-Tg) and in wild-type (WT) mice. Cytokine protein levels were assessed in the PFC by X-MAP technology. The influence of TLR4 signaling in LPS effects in both genotypes was assessed by pretreatment with the TLR4 antagonist (TAK-242, 3.0 mg/kg i.p.). Murine BV2 microglial cells were treated with PTN (0.5 μg/ml) and LPS (1.0 μg/ml) and assessed for the release of nitric oxide (NO).ResultsWe found that LPS-induced microglial activation is significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. The levels of TNF-α, IL-6, and MCP-1 in response to LPS were significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. Pretreatment with TAK-242 efficiently blocked increases in cytokine contents in a similar manner in both genotypes. Concomitant incubation of BV2 cells with LPS and PTN significantly potentiated the production of NO compared to cells only treated with LPS.ConclusionsOur findings identify for the first time that PTN is a novel and potent regulator of neuroinflammation. Pleiotrophin potentiates LPS-stimulated microglia activation. Our results suggest that regulation of the PTN signaling pathways may constitute new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN cerebral levels and neuroinflammation.
Highlights
Pleiotrophin (PTN) is a cytokine found highly upregulated in the brain in different disorders characterized by overt neuroinflammation such as neurodegenerative diseases, drug addiction, traumatic injury, and ischemia
Since previous studies suggest a possible contribution of PTN to Toll-like receptor 4 (TLR4)-mediated immune response [22] and TLR4 plays a pivotal role in neuroinflammation, we have investigated the possible differential contribution of TLR4 to the neuroinflammatory processes induced by LPS in both genotypes
LPS treatment tended to increase the number of glial fibrillary acidic protein (GFAP)+ astrocytes in the prefrontal cortex (PFC) of WT mice, being these cells characterized by large densely stained cell bodies as well as long and extensive processes compared to saline-treated animals (Fig. 1)
Summary
Pleiotrophin (PTN) is a cytokine found highly upregulated in the brain in different disorders characterized by overt neuroinflammation such as neurodegenerative diseases, drug addiction, traumatic injury, and ischemia. Within the central nervous system (CNS), the two main players in neuroinflammation are glial cells: microglia, the resident macrophages in the CNS, Ever-growing evidence points to a key role of inflammatory processes in a broad spectrum of diseases including traumatic brain injury, chronic neurodegenerative diseases, neuropathic pain, ischemia, and neuropsychiatric disorders including drug addiction [5,6,7]. Fernández-Calle et al Journal of Neuroinflammation (2017) 14:46 Psychostimulants such as amphetamine and its derivatives cause neuroinflammation and limit neurogenesis and induce blood-brain barrier (BBB) damage [8, 9]. All these effects induced by amphetamines are important for the dopaminergic injury induced by these drugs in the nigrostriatal pathway [10], which is the same circuitry affected in Parkinson’s disease (PD). In the search for validation of new biomarkers and for the development of new drugs that could modulate the inflammatory processes underlying these and other diseases of the CNS [13], our strategy was to identify proteins with known regulatory functions in inflammation, whose levels of expression are upregulated after amphetamine administrations and in the neurodegenerative areas of the brain of PD patients
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