Dr Egle Solito

Impact of peripheral inflammation in the central immune response: immune cell trafficking across brain barriersAs the population's average age rapidly increases, so does the incidence of age-associated neurological disease. Hence, there is an urgent need to investigate the mechanisms of senescence and ageing to ameliorate the huge social and economic costs of “ageing welfare”. It was long thought that the brain was protected from systemic inflammation, but growing evidence shows that systemic inflammatory stimuli, such as infection, also trigger a central response. Many pathologies such as Diabetes and hypertension have been linked with cognitive impairment yet studies to date have failed to establish a direct link between traditional vascular risk factors. 

As the primary interface between the peripheral system and the brain, the blood-brain barrier is a major player in communication between the two compartments, and, alongside the major brain immune cell, the microglia, represent an ideal target system to investigate how peripheral disease and inflammation can affect brain function. We are particularly interested in identifying mechanisms and molecules responsible for the alteration of the BBB as well as the brain immune system. 

Lab Projects topics

Diet impact on cerebrovascular cell senescence: a risk factor for vascular dementia
An unhealthy diet, hypertension, and heart disease are the most common factors contributing to or accelerating vascular ageing and are thus major risk factors for brain vascular alterations (e.g. Vascular dementia VaD).  With our ageing population, cognitive decline is becoming an important co-morbidity in metabolic disorders. We have shown that young mice fed a high-fat high sugar diet exhibit chronic, low-grade inflammation, blood-brain barrier (BBB) leakage due to tight junction, and basal lamina disruption.This leads to the entry of peripheral immune cells and soluble factors into the brain parenchyma, resulting in glial activation and local inflammation. Most importantly, our data demonstrate that either pharmacological intervention or dietary reversal to a more balanced, healthy diet corrected the BBB leakage via stabilisation of tight junction assembly and the control of tissue inhibitor of metalloproteinase (TIMP-1) expression1. Moreover, we have shown that: 1) older patients with diet-induced type 2 diabetes (T2DM) present with brain vascular leakage, immune cell infiltration, and microglia activation, and 2) serum from T2DM patients significantly disrupt BBB function in vitro (Sheikh et al. FASEB J. 2022). 

Given these parallels with our murine studies, we hypothesise that consumption of a high-fat high-sugar diet in adult/old age may lead to progressive cerebral damage and cognitive impairment, effectively accelerating the ageing process. Moreover, we will explore whether dietary reversion interventions (as are clinically recommended for T2DM management) can contribute to ameliorating vascular damage, neuroinflammation, and cognitive impairment. In this project we aim to test the hypothesis that high fat-high sugar diet-induced low-grade inflammation, BBB damage, and microglial activation may trigger premature ageing and/or aggravate normal ageing, increasing susceptibility to VaD. Thus, we will further test the hypothesis that the progression of VaD can be controlled by the reversal of the high-fat-high-sugar diet intervention.

Pathophysiology of vascular dementia in the heart-brain axis
Vascular dementia (VaD) is an intracranial vessel disease and the second-most-common type of dementia. Not only cardiovascular risk factors consistently showed a strong association with dementia, but diverse cardiac diseases, including myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), and myocarditis have also been reported to increase the risk of dementia. Coronary artery disease may lead to dementia through its association with brain small vessel disease. Small vessel disease, in turn, disturbs cerebral blood flow (CBF) regulation and perfusion disrupts the blood–brain barrier and leads to an increased susceptibility to neurological insults. Blood vessels provide the vital infrastructure for the delivery of oxygen and essential nutrients throughout the body, and the term “blood-brain barrier” (BBB) is used to describe the unique characteristics of the blood vessels that vascularize the central nervous system. 

Multiple mediators such as oxidative injury, inflammatory, autoimmune mechanisms, and genetic predisposition have been proposed to play a role in vascular dementia.
However, the lack of early diagnosis and therapies highpoint the importance of identifying and controlling immune and vascular factors in heart diseases (e.g., atrial fibrillation) early in life to prevent dementia.

This project’s main aim is to identify circulating factors (e.g., fibrinogen, cytokines) that would damage the cerebral endothelium focusing particularly on the BBB and studying the interplay between the immune system and the BBB in VaD.

COVID 19 Long-Term Impact on the Brain. A Study at the Interface of the Cerebral Vasculature and Immune System 
Long COVID, known as ‘post-acute sequelae of COVID-19’, affects multiple body systems including the CNS, and causes prolonged acute and severe symptoms following infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At least 65 million people worldwide have long COVID, with more than 651 million cases of COVID-19 documented worldwide. Furthermore, a proportion of long COVID patients develop Myalgic Encephalomyelitis, a chronic autoimmune condition with neurological and immunological symptoms.

The WHO has declared COVID-19 an endemic, no longer representing a global health emergency. However, the threat of new variants capable of causing surges in disease remains. It is clear with the lack of diagnostic biomarkers or treatment options; this number will only increase.

A main feature of long COVID is neurological symptoms, which develop during or following SARS-CoV-2 infection. Persistent cognitive impairment called COVID-19 ‘brain fog’ is prominent amongst lasting neurological symptoms, characterised by impaired memory and brain functioning. SARS-CoV-2 infection is demonstrated to be linked with a reduction in grey matter thickness of the orbitofrontal cortex, an area of the brain important for cognition, in a landmark UK biobank study. 
The cerebral vascular system comprises blood vessels essential for brain function, there are approximately 400 miles of capillaries in the brain. The Blood-Brain barrier (BBB), at the capillary level, protects the brain from potentially harmful circulating substances infiltrating into the brain parenchyma.

Through post-mortem studies, the mechanisms for brain fog are thought to be that of BBB leakage, inducing activation microglial, the resident innate immune cells in the brain, and the induction of reactivity in astrocytes, triggering the release of damaging reactive oxygen species (ROS). Activated microglia are recognised as a hallmark of neuroinflammation. Neuro-inflammation is also characterised by increased cytokines and chemokines in the cerebrospinal fluid that bathes the brain. Ultimately this leads to neuron loss and neural circuit dysfunction. The AIM of this project is to identify changes in the regulation of BBB components and expression of activated microglia, understand how circulating factor (e.g. cytokines) induced by COVID-19 affects barrier permeability, and define the role of innate/adaptive immune cells in CNS.