Correlating brain and systemic inflammation with ocular immune activation in mice and humans following stroke

Any major trauma or disease affecting the brain, such as stroke, is often associated with subtle, widespread inflammatory changes that are evident both in the brain, and in the blood circulation. Understanding how the immune system responds following stroke is key to identifying critical periods for treatment and for monitoring response to therapy that has an immunological basis. The degree of brain inflammation can be measured in patients following stroke using techniques such as positron emission tomography (PET) imaging however this is expensive and invasive, involving injections of radiopharmaceuticals, which can challenging for already vulnerable patients. In the last two decades, there has been remarkable progress in the development of imaging technologies that can enable visualisation of immune cells in the eye. The eye is an outpocket of the brain, and thus is an ideal organ to study to gain insights into the immune status of an individual.

The eye contains two major tissues that can be non-invasively imaged by clinicians and researchers: the retina and the cornea. The retinal and brain immune systems are closely linked, with both containing immune cells that share similar developmental origins. The cornea is a transparent connective tissue that is densely innervated by the peripheral nervous system, and a distinct population of immune cells that are equipped to living in a uniquely transparent and exposed tissue at the surface of the eye. We have recently shown that corneal immune cells are physically intertwined with sensory nerves whose ganglions reside in the brain, and are highly sensitive to brain-derived inflammation and neurodegeneration. Our laboratory has reported striking changes to the shape of corneal immune cells morphology in an experimental model of dementia; these immune cell changes occurred before the onset of corneal sensory nerve loss, and dementia-related brain pathology. These findings suggest that the cornea could serve as a useful and highly accessible peripheral organ to assess and observe the inflammatory status of stroke-related brain inflammation. Using a non-invasive confocal camera in A/Prof Downie's laboratory at the University of Melbourne, we have found that corneal immune cell morphology is altered in patients with mild cognitive impairment compared to healthy controls; these data provide strong evidence that the corneal immune cells reflect inflammation in the brain and systemic circulation.

This project will use an experimental model of stroke to ask the question of whether ocular immune cells can be used as surrogate markers of brain neuroinflammation. Markers of brain and blood inflammation will be correlated with corneal and retinal inflammation by comparing the type and shape of immune cells in the three tissues. This project will also examine novel markers of ocular inflammation in a clinical imaging study involving stroke patients, to determine if ocular imaging of immune cells can provide insights into the degree of post-stroke inflammation, which is a risk factor for developing secondary conditions such as dementia. Techniques will include high throughput flow cytometry and confocal microscopy, and sophisticated image analysis of immune cells in the eyes of experimental models, and human eyes.