Immune surveillance: lessons from meningeal endothelial cells and bisphosphonates

Abstract

Endothelial cells (ECs) line blood vessels throughout the body and are functionally specialized to sense and respond to signals in circulation. Therefore, these sentinel cells play critical roles in tissue immune surveillance by regulating recruitment of circulating leukocytes both at rest and during inflammation. Following the (re)-discovery of lymphatic vessels in the meningeal tissues enveloping the CNS parenchyma, growing number of studies are highlighting the importance of meningeal immunity in CNS immune surveillance. However, how meningeal ECs help regulate leukocyte recruitment at rest and during inflammation is not well understood.

Using a novel leukocyte tracking assay, we first determined that circulating leukocytes were recruited more abundantly to the dural than pial layer of the meninges at rest. RNA sequencing demonstrated that dural BECs had enriched expression of a unique set of molecules that can facilitate leukocyte recruitment. We determined P-selectin to be constitutively expressed on luminal surface of dural venule and venous sinus and functionally important for recruitment of monocytes. Despite differences at rest, we discovered both pial and dural BECs to be exquisitely sensitive to ultra-low circulating levels of lipopolysaccharide (LPS) and Gram-negative bacteria. Meningeal response to LPS and bacteria were dependent on CD14 and resulted in rapid but transient recruitment of monocytes. Lastly, using bone marrow chimeras, we uncovered sets of genes uniquely regulated by direct CD14-mediated LPS sensing in meningeal BECs. Taken together, we describe two novel mechanisms by which meningeal endothelium serves as a dynamic barrier that selectively allows recruitment of certain leukocyte populations at rest and rapidly respond to low grade endotoxemia and bacteremia by mounting a unique monocyte-predominant innate immune response.

Lastly, as the world was confronted with the challenges of the COVID-19 pandemic, we had the unique opportunity to access insurance claims data to identify potential medications that could be repurposed to be used in SARS-CoV-2 infection. Specifically, we examined bisphosphonates and discovered a robust association between prior bisphosphonate use and decreased odds of testing for SARS-CoV-2, COVID-19 diagnosis, and COVID-19 related hospitalization.