Accumulating evidence suggests a pivotal role of PDGFRß positive cells, a specific marker for central nervous system (CNS) pericytes, in tissue scarring. Identification of cells that contribute to tissue reorganization in the CNS upon injury is a crucial step to develop novel treatment strategies in regenerative medicine. It has been shown that pericytes contribute to scar formation in the spinal cord. It is further known that ischemia initially triggers pericyte loss in vivo, whilst brain trauma is capable of inducing pericyte detachment from cerebral vessels. These data point towards a significant role of pericytes in CNS injury. The temporal and spatial dynamics of PDGFRß cells and their responses in traumatic brain injury are poorly understood. Here we show that PDGFRß positive cells initially decline in the acute phase following experimental traumatic brain injury. However, PDGFRß positive cells increase significantly in the trauma zone days after brain injury. Using various pericyte markers we identify these cells to be pericytes that are demarcated by reactive gliosis. Our data indicate that brain trauma causes a biphasic response of pericytes in the early phase of brain trauma that may be of relevance for the understanding of pathological cellular responses in traumatic brain injury.

After traumatic brain injury (TBI) cerebral inflammation with invasion of neutrophils and lymphocytes is a crucial factor in the process of secondary brain damage. In TBI the intrinsic renin-angiotensin system is an important mediator of cerebral inflammation, as inhibition of the angiotensin II receptor type 1 (AT1) reduces secondary brain damage and the invasion of neutrophil granulocytes into injured cerebral tissue. The current study explored the involvement of immune cells in neuroprotection mediated by AT1 inhibition following experimental TBI. Four different cohorts of male mice were examined, investigating the effects of neutropenia (anti-Ly6G antibody mediated neutrophil depletion; C57BL/6), lymphopenia (RAG1 deficiency, RAG1−/−), and their combination with candesartan-mediated AT1 inhibition. The present results showed that reduction of neutrophils and lymphocytes, as well as AT1 inhibition in wild type and RAG1−/− mice, reduced brain damage and neuroinflammation after TBI. However, in neutropenic mice, candesartan did not have an effect. Interestingly, AT1 inhibition was found to be neuroprotective in RAG1−/− mice but not in neutropenic mice. The findings suggest that AT1 inhibition may exert neuroprotection by reducing the inflammation caused by neutrophils, ultimately leading to a decrease in their invasion into cerebral tissue.

Background: Cerebral inflammation with invasion of neutrophils and lymphocytes is an important factor in the process of secondary brain damage expansion after traumatic brain injury (TBI). Depletion of neutrophils in mice has been shown to reduce neurologic impairment after TBI. The intrinsic cerebral renin-angiotensin system is an important mediator of cerebral inflammation, as inhibition of the angiotensin II receptor type 1 (AT1) with candesartan improves neurologic recovery, and reduces secondary brain damage and cerebral neutrophil invasion after TBI. The present study was therefore designed to determine the role of immune cells in AT1 inhibition-mediated neuroprotection after TBI. Methods: In study A we assessed the effect of neutrophil depletion in mice after TBI. In study B we investigated the impact of RAG1 deficiency (RAG1-/-; mice without mature B- and T-lymphocytes) after TBI. In study C we investigated the role of neutrophils in candesartan mediated protection after TBI in wild-type mice with and without neutrophil depletion. In study D we examined the role of lymphocytes in AT1 inhibition mediated neuroprotection after TBI in RAG1-/-.Results: Neutropenic and RAG1-/- mice showed reduced brain damage compared to control groups. In control antibody treated wild type mice AT1 inhibition reduced lesion volumes and inflammation compared to vehicle, while in neutropenic mice, candesartan had no effect. In RAG1-/- mice AT1 inhibition resulted in reduction of brain damage and neuroinflammation compared to vehicle group. Conclusion: The present results demonstrate, that reduction of neutrophils and of lymphocytes as well as AT1 inhibition in wild type and RAG1-/- mice reduce brain damage and inflammation after TBI. However, AT1 inhibition was neuroprotective in RAG1-/- mice, but not in neutropenic mice. Therefore, the results indicate that AT1 inhibition mediated neuroprotection may be exerted by anti-inflammatory effects on neutrophils, with a subsequent reduction of neutrophil invasion.

Cerebral inflammation with invasion of neutrophils and lymphocytes is a crucial factor in the process of secondary brain damage after traumatic brain injury (TBI). In TBI the intrinsic renin-angiotensin system is an important mediator of cerebral inflammation, as inhibition of the angiotensin II receptor type 1 (AT1) reduces secondary brain damage and the invasion of neutrophil granulocytes into injured cerebral tissue. The present study investigated the role of immune cells in AT1 inhibition-mediated neuroprotection after experimental TBI. In four different cohorts, male mice were studied to examine effects of neutropenia (anti-Ly6G antibody mediated neutrophil depletion; C57BL/6) or lymphopenia (RAG1 deficiency, RAG1-/-) alone, or in combination with candesartan-mediated AT1 inhibition. The present results demonstrate that reduction of neutrophils (neutrophil depletion in wild type mice) and of lymphocytes (RAG1-/-) as well as AT1 inhibition in (control antibody treated) wild type and RAG1-/- mice reduce brain damage and neuroinflammation after TBI compared to control groups, while in neutropenic mice, candesartan had no effect. However, AT1 inhibition was neuroprotective in RAG1-/- mice, but not in neutropenic mice. Therefore, the results indicate that AT1 inhibition mediated neuroprotection may be exerted by anti-inflammatory effects on neutrophils, with a subsequent reduction of neutrophil invasion.