Trauma-induced expression of astrocytic thrombospondin-1 is regulated by P2 receptors coupled to protein kinase cascades

Abstract

Thrombospondin-1 (TSP-1) is an extracellular matrix protein produced by astrocytes, which can promote synaptogenesis. The regulation of astrocytic TSP-1 involves extracellular ATP through the activation of P2Y receptors coupled to various protein kinase signaling pathways. However, not much is known about the mechanisms regulating TSP-1 expression in primary cortical astrocytes after a traumatic brain injury. Using an in-vitro model of central nervous system trauma that stimulates the release of ATP, we found that trauma-induced expression and release of TSP-1 involved purinergic signaling as both expression and release were significantly attenuated by pyridoxalphosphate-6-azophenyl-2'-4'-disulfonic acid, a P2 receptor antagonist. Further antagonist studies with reactive blue 2 point to a role for P2Y4, as reactive blue 2 is a potent antagonist for rat P2Y4 receptors. In addition, the injury-induced expression of TSP-1 was significantly attenuated by the inhibition of extracellular signal-regulated kinase and p38/mitogen-activated protein kinase, whereas injury-induced release of TSP-1 was significantly blocked by the inhibition of extracellular signal-regulated kinase and Akt. Using an in-vivo model of a moderate parasagittal fluid-percussion brain injury, we found that TSP-1 levels were increased when compared with those in sham animals in the cortex, thalamus, and hippocampus. We conclude that TSP-1 expression after injury can be regulated by the activation of P2 receptors coupled with protein kinase signaling pathways and suggest that purinergic signaling, by regulating TSP expression, may play an important role in cell-matrix and cell-cell interactions such as those occurring during central nervous system repair.

The prognostic value of plasma thrombospondin-1 concentrations after aneurysmal subarachnoid hemorrhage

“…In addition, TSP-1 expression is upregulated in the cortex after focal cerebral ischemia/reperfusion [20] and traumatic or hemorrhagic brain injury [21,22] and in the rat spinal cord after injury [23]. It is also confirmed that thrombin promotes the expression of TSP-1 in a rat model of intracerebral hemorrhage [21].…”

“…In addition, astrocytic TSP-1 is involved in synaptogenesis [17] and has been implicated in neuronal dendritic growth and axonal sprouting [28,38]. The regulation of astrocytic TSP-1 by purinergic signaling suggests that purinergic signaling in astrocytes may play a vital role in the reorganization of synaptic networks after central nervous system injury, pointing to a key trophic role for astrocytes during and after brain trauma [22]. Because TSP-1 is a multifunctional molecule, much work may be required to make clear the exact effects of their expression.…”

“…In the central nervous system, reactive astrocytes can produce TSP-1 [18,19]. In addition, TSP-1 expression is upregulated in the cortex after focal cerebral ischemia/reperfusion [20] and traumatic or hemorrhagic brain injury [21,22] and in the rat spinal cord after injury [23]. Circulating TSP-1 concentrations are increased in coronary artery disease and diabetes and sickle cell disease [24,25].…”

Plasma thrombospondin-1 and clinical outcomes in traumatic brain injury

“…Moreover, TSP‐1 expression of animal cortex is upregulated after ischemic, traumatic, and hemorrhagic brain injury . It is also confirmed that thrombin promotes the expression of TSP‐1 in a rat model of intracerebral hemorrhage . Therefore, TSP‐1 may be released into the cerebrospinal fluid from damaged brain tissue and afterward escapes into the peripheral blood after brain injury.…”

Astrocyte-Secreted Matricellular Proteins in CNS Remodelling during Development and Disease

“…It is likely that several signaling pathways can stimulate TSP production in reactive astrocytes. For example, in an in vivo trauma model, TSP1 expression was induced by extracellular ATP (Adenosine triphosphate) via P2Y purinergic receptors and ERK (extracellular signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) signaling [119]. Additionally, TSP1 expression was activated by collagen-stimulated integrin signaling in reactive astrocytes following brain injury [120].…”