The benefits of neuroinflammation for the repair of the injured central nervous system

Inflammation of the nervous system(neuroinflammation)is now recognized as a hallmark of virtually all neurological disorders.In neuroinflammatory conditions such as multiple sclerosis,there is prominent infiltration and a long-lasting representation of various leukocyte subsets in the central nervous system(CNS)parenchyma.Even in classic neurodegenerative disorders,where such immense inflammatory infiltrates are absent,there is still evidence of activated CNS-intrinsic microglia.The consequences of excessive and uncontrolled neuroinflammation are injury and death to neural elements,which manifest as a heterogeneous set of neurological symptoms.However,it is now readily acknowledged,due to instructive studies from the peripheral nervous system and a large body of CNS literature,that aspects of the neuroinflammatory response can be beneficial for CNS outcomes.The recognized benefits of inflammation to the CNS include the preservation of CNS constituents(neuroprotection),the proliferation and maturation of various neural precursor populations,axonal regeneration,and the reformation of myelin on denuded axons.Herein,we highlight the benefits of neuroinflammation in fostering CNS recovery after neural injury using examples from multiple sclerosis,traumatic spinal cord injury,stroke,and Alzheimer’s disease.We focus on CNS regenerative responses,such as neurogenesis,axonal regeneration,and remyelination,and discuss the mechanisms by which neuroinflammation is pro-regenerative for the CNS.Finally,we highlight treatment strategies that harness the benefits of neuroinflammation for CNS regenerative responses.

Enhanced liver X receptor signalling reduces brain injury and promotes tissue regeneration following experimental intracerebral haemorrhage:roles of microglia/macrophages

background Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage(ICH).As a regulator of inflammation and lipid metabolism,Liver X receptor(LXR)has the potential to alter microglia/macrophage(M/M)phenotype,and assist tissue repair by promoting cholesterol efflux and recycling from phagocytes.To support potential clinical translation,the benefits of enhanced LXR signalling are examined in experimental ICH.Methods Collagenase-induced ICH mice were treated with the LXR agonist GW3965 or vehicle.Behavioural tests were conducted at multiple time points.Lesion and haematoma volume,and other brain parameters were assessed using multimodal MRI with T2-weighted,diffusion tensor imaging and dynamic contrast-enhanced MRI sequences.The fixed brain cryosections were stained and confocal microscopy was applied to detect LXR downstream genes,M/M phenotype,lipid/cholesterol-laden phagocytes,oligodendrocyte lineage cells and neural stem cells.Western blot and real-time qPCR were also used.CX3CR1^(CreER):Rosa26^(iDTR) mice were employed for M/M-depletion experiments.results GW3965 treatment reduced lesion volume and white matter injury,and promoted haematoma clearance.Treated mice upregulated LXR downstream genes including ABCA1 and Apolipoprotein E,and had reduced density of M/M that apparently shifted from proinflammatory interleukin-1β+to Arginase1+CD206+regulatory phenotype.Fewer cholesterol crystal or myelin debris-laden phagocytes were observed in GW3965 mice.LXR activation increased the number of Olig2+PDGFRα+precursors and Olig2+CC1+mature oligodendrocytes in perihaematomal regions,and elevated SOX2+or nestin+neural stem cells in lesion and subventricular zone.MRI results supported better lesion recovery by GW3965,and this was corroborated by return to pre-ICH values of functional rotarod activity.The therapeutic effects of GW3965 were abrogated by M/M depletion in CX3CR1^(CreER):Rosa26^(iDTR) mice.Conclusions LXR agonism using GW3965 reduced brain injury,promoted beneficial properties of M/M and facilitated tissue repair correspondent with enhanced cholesterol recycling.