PROS1 and TAM signaling drive key developmental, homeostatic and disease mechanisms in microglia
2Institute for Drug Research, Department of Pharmacology, The Hebrew University, Israel
The TAMs (Tyro3, Axl and MerTK) are a family of tyrosine kinase receptors regulating several mechanisms in the Central Nervous System (CNS), immune, vascular and reproductive systems. The TAMs ligand Protein S (PROS1), mainly known as a potent blood anti-coagulant, is also expressed by most brain cells. These include microglia, the local innate immune cells and professional phagocytes.
Our previous data identified neuronal PROS1 as a regulator of Neural Stem Cells (NSCs) self-renewal and differentiation. Moreover, PROS1 was found to be anti-inflammatory in macrophages. Now, our goal is to understand how PROS1 contributes to microglia’s dual role of neuroglia and immune cells. For this, the Pros1 gene was ablated in the mouse myeloid lineage (Pros1cKO).
Compared to controls, Pros1cKO mice exhibit altered microglial proliferation and increased apoptosis, resulting in lower microglia coverage at steady state (post-natal day 60). At this time point, microglial PROS1 also negatively regulates neuronal proliferation and neurogenesis.
In the immune system, PROS1 dampens inflammation by reducing cytokine production and promoting phagocytosis. The uptake of apoptotic neurons (ANs) and myelin is compromised in Pros1cKO primary microglia. Similarly, we observe accumulation of ANs in post-natal Pros1cKO brains, and of myelin debris following Traumatic Brain Injury (TBI).
Taken together, we conclude that PROS1 plays key roles in microglial and neuronal development; moreover, PROS1 has anti-inflammatory activity by driving tissue clearance both in health and following TBI, thereby promoting tissue repair.