The concept of the CNS as an immune-privileged organ has led to a common misunderstanding that it is not an active immunological organ, guarded from its surroundings by the blood-brain barrier (BBB). Recent advances in this field clearly demonstrate that the CNS is a highly immunologically active organ, with complex immune responses mostly based on innate immune processes. Such responses implicate a continuum of heterogeneous cell types both inside the CNS, in the periphery, and at their interface, the BBB. This Review aims to discuss the importance of the BBB as the first line of defense against brain infections and injuries of the CNS and the main molecular mechanisms involved in the control of the innate immune system of the CNS. We also review the central role of the neurovascular unit in diseases of the CNS and how it can be targeted for novel therapeutic strategies.

The promotion of post-ischaemic motor recovery remains a major challenge in clinical neurology. Recently, plasticity-promoting effects have been described for the growth factor erythropoietin in animal models of neurodegenerative diseases. To elucidate erythropoietin's effects in the post-acute ischaemic brain, we examined how this growth factor influences functional neurological recovery, perilesional tissue remodelling and axonal sprouting of the corticorubral and corticobulbar tracts, when administered intra-cerebroventricularly starting 3 days after 30 min of middle cerebral artery occlusion. Erythropoietin administered at 10 IU/day (but not at 1 IU/day), increased grip strength of the contralesional paretic forelimb and improved motor coordination without influencing spontaneous locomotor activity and exploration behaviour. Neurological recovery by erythropoietin was associated with structural remodelling of ischaemic brain tissue, reflected by enhanced neuronal survival, increased angiogenesis and decreased reactive astrogliosis that resulted in reduced scar formation. Enhanced axonal sprouting from the ipsilesional pyramidal tract into the brainstem was observed in vehicle-treated ischaemic compared with non-ischaemic animals, as shown by injection of dextran amines into both motor cortices. Despite successful remodelling of the perilesional tissue, erythropoietin enhanced axonal sprouting of the contralesional, but not ipsilesional pyramidal tract at the level of the red and facial nuclei. Moreover, molecular biological and histochemical studies revealed broad anti-inflammatory effects of erythropoietin in both hemispheres together with expression changes of plasticity-related molecules that facilitated contralesional axonal growth. Our study establishes a plasticity-promoting effect of erythropoietin after stroke, indicating that erythropoietin acts via recruitment of contralesional rather than of ipsilesional pyramidal tract projections.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting older people worldwide. It is a progressive disorder mainly characterized by the presence of amyloid-beta (Aβ) plaques and neurofibrillary tangles within the brain parenchyma. It is now well accepted that neuroinflammation constitutes an important feature in AD, wherein the exact role of innate immunity remains unclear. Although innate immune cells are at the forefront to protect the brain in the presence of toxic molecules including Aβ, this natural defense mechanism seems insufficient in AD patients. Monocytes are a key component of the innate immune system and they play multiple roles, such as the removal of debris and dead cells via phagocytosis. These cells respond quickly and mobilize toward the inflamed site, where they proliferate and differentiate into macrophages in response to inflammatory signals. Many studies have underlined the ability of circulating and infiltrating monocytes to clear vascular Aβ microaggregates and parenchymal Aβ deposits respectively, which are very important features of AD. On the other hand, microglia are the resident immune cells of the brain and they play multiple physiological roles, including maintenance of the brain’s microenvironment homeostasis. In the injured brain, activated microglia migrate to the inflamed site, where they remove neurotoxic elements by phagocytosis. However, aged resident microglia are less efficient than their circulating sister immune cells in eliminating Aβ deposits from the brain parenchyma, thus underlining the importance to further investigate the functions of these innate immune cells in AD. The present review summarizes current knowledge on the role of monocytes and microglia in AD and how these cells can be mobilized to prevent and treat the disease.

Novel therapeutic concepts against cerebral ischemia focus on cell-based therapies in order to overcome some of the side effects of thrombolytic therapy. However, cell-based therapies are hampered because of restricted understanding regarding optimal cell transplantation routes and due to low survival rates of grafted cells. We therefore transplanted adult green fluorescence protein positive neural precursor cells (NPCs) either intravenously (systemic) or intrastriatally (intracerebrally) 6 hours after stroke in mice. To enhance survival of NPCs, cells were in vitro protein-transduced with TAT-heat shock protein 70 (Hsp70) before transplantation followed by a systematic analysis of brain injury and underlying mechanisms depending on cell delivery routes. Transduction of NPCs with TAT-Hsp70 resulted in increased intracerebral numbers of grafted NPCs after intracerebral but not after systemic transplantation. Whereas systemic delivery of either native or transduced NPCs yielded sustained neuroprotection and induced neurological recovery, only TAT-Hsp70-transduced NPCs prevented secondary neuronal degeneration after intracerebral delivery that was associated with enhanced functional outcome. Furthermore, intracerebral transplantation of TAT-Hsp70-transduced NPCs enhanced postischemic neurogenesis and induced sustained high levels of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor in vivo. Neuroprotection after intracerebral cell delivery correlated with the amount of surviving NPCs. On the contrary, systemic delivery of NPCs mediated acute neuroprotection via stabilization of the blood-brain-barrier, concomitant with reduced activation of matrix metalloprotease 9 and decreased formation of reactive oxygen species. Our findings imply two different mechanisms of action of intracerebrally and systemically transplanted NPCs, indicating that systemic NPC delivery might be more feasible for translational stroke concepts, lacking a need of in vitro manipulation of NPCs to induce long-term neuroprotection.