Table 2.

Brain injury-mediated chronic neuroinflammatory response and neurodegeneration after the brain injury/TBI

Brain injury Causes: Direct blow to the skull, penetrating injury, acceleration, deceleration, rotational forces, Ischemic, hemorrhagic or traumatic injuries Injured brain cells: Neurons, astrocytes, microglia, ependymal cells, oligodendrocytes, endothelial cells Clinical complications: Hematoma, subarachnoid hemorrhage, contusion, diffuse axonal injury, cerebral ischemia, increased intracranial pressure, neuroinflammation, neurodegeneration, sickness behavior

Neuroinflammatory responses in brain injury  Disruption of tight junction proteins and integrity of basement membrane  Increased BBB permeability, edema, neuroinflammation  Neutrophil, macrophage, T-cell and mast cells recruitment into the injured site  Incomplete removal of dead cells and debris  Partial wound healing and tissue remodeling  Insignificant axonal regrowth  Aβ 1–42 deposition, amyloid plaque and NFTs formation in the brain

Neuroinflammatory cells and their functional status in brain injury  Microglia (M1 proinflammatory), resting ramified microglia to Reactive/activated microglia (amoeboid), migration, phagocytosis, antigen presentation  Astrocytes (A1 proinflammatory), reactive astrocytes, reactive gliosis, retraction of process from synapsis, increased GFAP, S100β and vimentin, increase in metabolic enzymes  Neutrophils – phagocytosis, MMPs release.  Mast cells – degranulated and activated mast cell types  T-cells – activated T-cells.  Endothelial cells – activated cells  Macrophage (M1-like) – activated cells  BBB, BCSFB – increased permeability

Brain injury and expression of neuroinflammatory mediators and receptors in the CNS/immune cells Microglia (M1) - activation, proliferation, phagocytosis, DAMPs (ATP, DNA, RNA), CCL2, IL-1β, TNF-α, IL-6, IL-8, IL-12, IL-23, IL-33, ROS, glutamate, MMPs, TLRs, PAR-2, P2, NO, TREM2 Astrocytes (A1) - CCL2, IL-1β, TNF-α, IL-6, GM-CSF, ROS, glutamate, MMPs, VEGFA, GFAP, S100β Neurons - MMPs, VEGFA, P2, arginine vasopressin, PAR-2 Endothelial cells – ICAM-1, VCAM-1, CCL2, NO, MMPs, VEGFR1, VEGFR2, TLRs, PTY2, arginine vasopressin Mast cells - degranulation - prestored TNF-α, histamine, proteases, GM-CSF, IL-4 Mast cells – activated - newly formed prostaglandins, leukotrienes, growth factors, TNF-α, IL-1α, IL-6, IL-8, IL-18, IL-23, IL-33, CCL2, VEGF, neurotrophins, substance P, CRH T-cells – IL-4, IL-21 Platelets – TGF-β Neutrophils - MMP9, TNF-α, ROS, elastase (ELANE) Astrocytes, neurons and inflammatory cells- thrombin, albumin, fibrinogen, Ca++ increase, ERK1/2, p38, JNK MAPKs; p13K/Akt, NF-kB, AP-1; TREM2, Apoε4, PAR1–3 and 4, ATP, UTP, purinoceptors

Abbreviations: AP-1, activator protein 1; Apoε4, apolipoprotein E4; 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; DAMPs, damage-associated molecular patterns; ERK1/2, extracellular signal-regulated kinases; GFAP, glial fibrillary acidic protein; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-1apha, interleukin-1α; ICAM-1, intercellular adhesion molecule-1; JNK, c-jun N-terminal kinase; MAPKs, mitogen-activated protein kinase; MMP9, matrix metalloproteinase 9; NO, NF-κB, nuclear factor kappa-B; NO, nitric oxide; NFTs, neurofibrillary tangles; PAMs, pathogen-associated molecular pattern; PDGF, platelet-derived growth factor; PAR, protease activated receptor; ROS, reactive oxygen species; PRR, pattern recognition receptors; TGF-beta, transforming growth factor-β; TLRs, toll-like receptors; TNF-α, tumor necrosis factor-alpha; TREM2, Triggering receptor expressed on myeloid cells 2; VCAM-1, vascular cell adhesion molecule 1; VEGF A, vascular endothelial growth factor A; VEGFR, vascular endothelial growth factor receptor.