Table 1.

Normal neuroprotective immunosurveillance by innate immune cells in the normal healthy brain

Normal immunosurveillance in the brain Microglia: acts as house keepers - resident innate immune cell - constantly perform immunusurveillance by migration, phagocytic and antigen presentation - release cytotoxic hydrogen peroxide and nitric oxide - cytokines and chemokines & maintain normal brain homeostasis - tissue repair mechanisms - influence neuronal survival - neurotransmitter release - maintenance of synapses - promote synaptogenesis - synaptic scaling - regulate BBB Astrocytes: A2 astrocytes acts as supporting cells and protect neurons, astrocytic process support BBB formation and its integrity - regulate endothelial transport of substances - guide axon and neurite outgrowth - secrete growth factors for neurons in embryonic stage and after an injury – synaptogenesis - synaptic plasticity, neurotransmitter synthesis - regulate cerebral blood flow - hormone synthesis - cell-cell communication. Naïve astrocytes express GFAP, S100 β, GLT-1, GLAST, reactive astrocytes express Nestin, MMP13, MMP2, Axin2, and scar forming astrocyte express Sox9, Acan, Pcan, Slit 2, Chst11, Cdh2

Neuroprotective cells, gliovascular unit (BBB + glia), neurovascular unit (BBB + neurons) in the brain Microglia normal (ramified M2) – A2 astrocytes - neutrophils – macrophage - mast cells - T-cells - endothelial cells - intact BBB and BCSFB

Cells and neuroprotection associated mediators and receptors in the brain Microglia (M2): DAMPs (ATP, DNA, RNA), CCL2, IL-1α, IL-4, IL-10, IL-13, TGF-β, VEGF, BDNF, PDGF, progranulin, CX3CR1 R, PAMPs, TLRs, PRR, CXCL1-CX3CR1, CD200R A2 Astrocytes: neurotrophin, CCL2, TREM2 Neurons: CD200, fractalkine (CX3CL1) Endothelial cells: ICAM-1, VCAM-1 Neutrophils: Phagocytosis, myeloperoxidase, TGF-β, NGF, GM-CSF, VEGF, IL-4, IL-10,ROS, MMP9, neutrophil and microglianeutrophils Mast cells: Important for wound healing and scar formation after an injury. TNF-α, histamine, proteases, GM-CSF, IL-4, serotonin, heparin and tryptase are prestored in granules. Newly synthetized are TNF-α, IL-1α, IL-6, IL-33, CCL2, VEGF (angiogenesis), substance P, CRH, TGF-β, NGF, prostaglandins, growth factors, leukotrienes T-cells: IL-4 Macrophages (M2): CCL2, TNF-α, IL-1α, IL-6

Acute protective immune response in the brain Neutrophils recruitment, removal of dead cells and debris, wound healing and tissue remodeling, and angiogenesis

Abbreviations: BBB, blood-brain barrier; BCSFB, BDNF, brain-derived neurotrophic factor; blood cerebrospinal fluid barrier; CCL2, chemokine (C-C motif) ligand 2; CRH, corticotropin releasing hormone; CXCR1, CXC3, chemokine receptor 1 and 3; DAMPs, damage-associated molecular patterns; IL-1apha, interleukin-1α; ICAM-1, intercellular adhesion molecule-1; PAMPs, pathogen-associated molecular pattern; PDGF, platelet-derived growth factor; PRR, pattern recognition receptors; TGF-beta, transforming growth factor-β; TLRs, toll-like receptors; TNF-α, tumor necrosis factor-alpha; GM-CSF, granulocyte-macrophage colony-stimulating factor; VCAM-1, vascular cell adhesion molecule 1; VEGF A, vascular endothelial growth factor A.