ICAM-1 Adhesion Molecules Facilitate Immune Cell Docking at the Cribriform Plate Perineural Microenvironment in Aging

Introduction/Rationale: With aging, the immune system releases pro-inflammatory factors causing chronic inflammation or “inflammaging”. Within the aged central nervous system (CNS), myeloid cell populations increase due to inflammation-induced myelopoiesis within skull bone marrow compartments. Decreased waste removal through CNS lymphatics worsens inflammation and immune cell buildup, leaving the CNS prone to neurodegenerative disorders. This highlights the need to study CNS drainage sites like the cribriform plate (CP). The CP is a sieve-like structure within the ethmoid bone that holds olfactory bulbs and nerves passing from the CNS to the nasal epithelium. The CP also enables cerebrospinal fluid and waste drainage into nasal lymphatics and olfactory nerves. Previously, our lab has identified that the CP perineural regions contain an immune microenvironment that changes during neuroinflammation. We have shown that CP bone channels connect the bone marrow to olfactory nerve bundles, facilitating immune cell migration into the perineural space. It is unknown how immune cells dock within the perineural niche, and how the perineural microenvironment differs with age.

Methods: Utilizing immunohistochemistry, flow cytometry, and 3D Light sheet fluorescent microscopy

Results: we show that (1) the aged perineural immune environment has an increase in CD11b+ myeloid cells. (2) ICAM1 (CD54) adhesion molecule expression, area, and mean fluorescent intensity increases with age, and identified ICAM-1 as the docking protein located perineurally on TUBB3+ olfactory nerve bundles at the CP in elderly mice and humans. We propose that the accumulation of myeloid cells contributes to nerve damage in aging. We study markers of death (caspase-3) and gliosis (GFAP) within the olfactory nerve bundles to test this hypothesis.

Conclusion: These findings help elucidate the role of ICAM-1 within olfactory nerves and highlights potential therapeutic use of localized ICAM-1 drug therapy to preserve CNS drainage and olfactory nerve health.