Abstract WP142: Targeting VCAM1 to Reduce Acute and Chronic Neuroinflammation After Stroke

Abstract

Background: Ischemia-induced neuroinflammmation is associated with worse outcomes after stroke. The innate immune response can mediate infarct expansion and impair short-term recovery, while adaptive responses lead to chronic neuroinflammation, neurodegeneration remote to the ischemic lesion, and consequent vascular dementia. Vascular cell adhesion molecule 1 (VCAM1) is an endothelial protein that facilitates vascular-immune cell interactions by binding very late antigen-4 (VLA-4). Soluble VCAM1 plasma levels are elevated in stroke patients and in aging people and mice. In aging mice, blocking VCAM1 ameliorates age-induced neuroinflammation and cognitive impairment. Objective: To determine if acute anti-VCAM1 treatment in mice would reduce microgliosis and astrogliosis, while delayed treatment would reduce B and T lymphocyte infiltration. Methodology: Adult (3-month-old) C57BL/6 mice (N=10/group) underwent permanent distal middle cerebral artery occlusion and were dosed with anti-VCAM1 antibody 4h post-stroke, then sacrificed at 72h. Microgliosis and astrogliosis were quantified as percent area immunostained in the infarct border by Iba1 and GFAP, respectively. Results: Acute treatment reduced microgliosis by 30% (p=0.0476) and astrogliosis 39% (p<0.03). Additionally, adult mice (N=10/group) were treated with anti-VCAM1 immediately (4h) or later (4d) post-stroke and euthanized 3 weeks later. B cell infiltration was quantified as percent stroke core immunostained by B220, while T lymphocyte infiltration was quantified as CD3+ cells in the core. Delayed anti-VCAM1 significantly reduced B and T cell infiltration by approximately 25% (p=0.0015) and 50% (p=0.0192), respectively. In contrast, early anti-VCAM1 had no effect on B/T cell infiltration. Conclusions: Together, these findings establish VCAM1 as a possible therapeutic target to prevent stroke-induced neuroinflammation in both acute and chronic settings.