Abstract
Intercellular adhesion molecule-1 (ICAM-1) promotes adhesion and transmigration of circulating leukocytes across the blood-brain barrier (BBB). Traumatic brain injury (TBI) causes transmigrated immunocompetent cells to release mediators [function-associated antigen (LFA)-1 and macrophage-1 antigen (Mac-1)] that stimulate glial and endothelial cells to express ICAM-1 and release cytokines, sustaining neuroinflammation and neurodegeneration. Although a strong correlation exists between TBI-mediated inflammation and impairment in functional outcome following brain trauma, the role of ICAM-1 in impairing functional outcome by inducing neuroinflammation and neurodegeneration after TBI remains inconclusive. The experimental TBI was induced in vivo by fluid percussion injury (FPI; 10 and 20 psi) in wild-type (WT) and ICAM-1-/- mice and in vitro by stretch injury (3 psi) in brain endothelial cells. We manipulate ICAM-1 pharmacologically and genetically and conducted several biochemical analyses to gain insight into the mechanisms underlying ICAM-1-mediated neuroinflammation and performed rotarod, grid-walk, sucrose preference, and light-dark tests to assess functional outcome. TBI-induced ICAM-1-mediated neuroinflammation and cell death occur via LFA-1 or Mac-1 signaling pathways that rely on oxidative stress, matrix metalloproteinase (MMP), and vascular endothelial growth factor (VEGF) pathways. The deletion or blocking of ICAM-1 resulted in a better outcome in attenuating neuroinflammation and cell death as marked by the markers such as NF-kB, IL-1β, TNF-α, cleaved-caspase-3 (cl-caspase-3), Annexin V, and by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and Trypan blue staining. ICAM-1 deletion in TBI improves sensorimotor, depression, and anxiety-like behavior with significant upregulation of norepinephrine (NE), dopamine (DA) D1 receptor (DAD1R), serotonin (5-HT)1AR, and neuropeptide Y (NPY). This study could establish the significance of ICAM-1 as a novel therapeutic target against the pathophysiology to establish functional recovery after TBI.