Pericyte dysfunction in blood brain barrier impairment caused by HIV infection (278.1)

Abstract

Studies performed over the last decade indicated that functional alterations of brain endothelium is the main factor in blood brain barrier (BBB) injury during HIV infection. However, other cells constituting the BBB (like pericytes) received almost no attention. We propose that pericyte dysfunction present in HIV infection can contribute to BBB compromise and progression of HIV‐associated neurocognitive disorders (HAND). We used co‐cultures of primary human brain pericytes (BP) and human primary brain micsovascular endothelial cells (BMVEC) and human brain tissues of HIV infected patients to study alterations of pericyte function in chronic neuroinflammation driven by HIV infection. We found partial pericyte loss and down‐regulation of key receptors on these cells in brain tissue of HIV infected patients (even without detectable HIV in the brain) and in HIV infected ‘humanized’ mice that paralleled BBB compromise and neuroinflammation. BP treated with IL‐1β or TNFα demonstrated decreased secretion of angiopoetin 1 and transforming growth factor‐β1, diminished expression of platelet derived growth factor‐B receptor β1 and connexin 43 (critical for pericyte recruitment to BBB and gap junctions between BP and BMVEC). BP exposed to IL‐1β/TNFα showed enhanced expression of numerous pro‐inflammatory factors (relevant to HIV neuropathogenesis) and adhesion molecules paralleling increased adhesion of monocytes to pericyte monolayers. Using BBB models (composed of BMVEC‐BP), we showed increased monocyte migration across BBB constructs in response to the relevant chemokine, CCL2. IL‐1β/TNFα treatment of pericytes altered their ability to spread or migrate providing a potential mechanism for their decrease in brain tissue of HIV‐infected patients. These data point to a major decrease in barrier‐supporting function and enhanced inflammatory responses in brain pericytes after exposure to relevant cytokines and in brain tissues of HAND patients.Grant Funding Source: supported by NIH grants MH65151, AA015913