The effect of peripheral inflammation on cortical lesions is independent of blood brain barrier integrity

FARIAS M.I; FERNANDO PITOSSI; BERENICE SILVA; AVALOS, JUAN CARLOS; FERRARI , CC; LEAL, MARÍA C.; MIGLIETTA, ESTEBAN

Congreso; European Charcot Foundation; 2020

Background: Multiple Sclerosis (MS) is associated with inflammation and blood brain barrier (BBB) breakdown. The disruption of the BBB is linked with recruitment of inflammatory cells to the central nervous system from peripheral circulation. In the Progressive Forms of MS (PFMS), the BBB is intact, which suggests a trapped inflammatory process within the lesion. Self-sustained inflammation is progressively built up in meningeal as well as white and grey matter perivascular spaces. Therefore, the role of the closed BBB is still unknown.Objectives: To study the response of repaired inflammatory lesion in the cortex trapped within a recovered BBB after peripheral pro-inflammatory stimulation.Methods: Focal chronic cortical lesions were induced in adult rats by the long term expression of interleukin 1 beta (IL-1b) using adenovectors. Systemic inflammation was induced by intravenously injection of the same adenovector. We performed behavioral tests to assess anxiety and short-term memory impairment and analysed cortico-meningeal response using immunohistochemistry techniques. We also performed brain magnetic resonance imaging (MRI).Results: Chronic expression of IL-1b in the cortex induced focal cortical lesion characterized by BBB breakdown, macrophages and neutrophil recruitment (not lymphocytes), demyelination, glial activation, neurodegeneration, and meningeal inflammation; associated with cognitive impairment (CI). At 56 dpi, these lesions evolved to a small scar composed mostly of microglia/macrophages and inflammatory infiltrate, located preferentially around the lumen of the blood vessels, the BBB was restored and the associated behavioural changes disappeared. Peripheral stimulation at 56 dpi recrudesced the lesions, which showed recruitment of lymphocytes (not neutrophils), demyelination, neurodegeneration and meningeal inflammation. In addition, BBB was disrupted after the peripheral stimulation and cognitive impairment and anxiety-like symptoms returned. These reactivated lesions could not be visualized by MRI.Conclusions: Systemic stimulation disrupted the BBB, flared up the central inflammatory process and changed the status of the trapped inflammatory lesion within the closed BBB to an adaptive inflammatory response. In addition, the behavioural symptoms reappear. The study of the impact of systemic inflammation would help to elucidate the mechanisms involved in the evolution of these cortical lesions.