Human brain pericytes as mediators of neuroinflammation: Implications for disease and therapeutics

Abstract

Chronic neuroinflammation contributes to the development and progression of almost all neurological disorders and brain pericytes participate in immune responses through cytokine and chemokine secretion, adhesion molecule expression, reactive oxidative species production, and phagocytic ability. The unique perivascular location of pericytes makes these cells ideally positioned to control numerous aspects of the central nervous system (CNS) immune response; including leucocyte extravasation, inflammation-induced blood-brain barrier (BBB) disruption, phagocytic clearance of waste products, and paracrine-signalling with parenchymal brain cells, including microglia. Utilising in vitro cultures of pericytes derived from adult human brain biopsy tissue, this thesis sought to characterise novel mechanisms by which pericytes can contribute to neuroinflammation and identify methods to control these responses. In particular, it was found that the transcription factor C/EBPδ is induced following immune challenge and attenuates the expression of critical mediators of leucocyte extravasation. Similarly, it was identified that whilst the cytokine TGFβ1 may reduce immune cell infiltration through attenuated chemokine and adhesion molecule expression, it contributes to several processes involved in BBB dysfunction. A contribution for culture media in modifying the pericyte phenotype and several prototypical functions of pericytes in vitro, including their innate immune responses, was also established. Next, a role for pericytes as CNS macrophages was identified and their ability to phagocytose and process amyloid-beta aggregates present in the Alzheimer’s disease brain is shown. Lastly, a novel method to efficiently isolate primary microglia with preserved phenotypes from the adult human brain is described and these cultures were used to demonstrate an immunomodulatory function of pericytes through limiting microglial-mediated inflammation. Taken together, these data describe an extensive and unappreciated contribution of brain pericytes to neuroinflammation and identify attractive mechanisms to manipulate these functions. As neuroinflammation is present in almost all neurological disorders, targeting various aspects of pericyte-mediated immune responses may offer therapeutic benefits for the treatment or prevention of a range of devastating neurological conditions.