TAM Receptor Pathways at the Crossroads of Neuroinflammation and Neurodegeneration

Abstract

Increasing evidence suggests that pathogenic mechanisms underlying neurodegeneration are strongly linked with neuroinflammatory responses. Tyro3, Axl, and Mertk (TAM receptors) constitute a subgroup of the receptor tyrosine kinase family, cell surface receptors which transmit signals from the extracellular space to the cytoplasm and nucleus. TAM receptors and the corresponding ligands, Growth Arrest Specific 6 and Protein S, are expressed in different tissues, including the nervous system, playing complex roles in tissue repair, inflammation and cell survival, proliferation, and migration. In the nervous system, TAM receptor signalling modulates neurogenesis and neuronal migration, synaptic plasticity, microglial activation, phagocytosis, myelination, and peripheral nerve repair, resulting in potential interest in neuroinflammatory and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Multiple Sclerosis. In Alzheimer and Parkinson diseases, a role of TAM receptors in neuronal survival and pathological protein aggregate clearance has been suggested, while in Multiple Sclerosis TAM receptors are involved in myelination and demyelination processes. To better clarify roles and pathways involving TAM receptors may have important therapeutic implications, given the fine modulation of multiple molecular processes which could be reached. In this review, we summarise the roles of TAM receptors in the central nervous system, focusing on the regulation of immune responses and microglial activities and analysing in vitro and in vivo studies regarding TAM signalling involvement in neurodegeneration.

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

“…Because we collected sufficient microglia for DEG analysis, we sought a clearer understanding of the functional ramifications of their COVID-19 activation. As expected, established markers of microglial activation previously linked to pathologic functions such as CD74 and MERTK were strongly upregulated 67–74 . We observed a concomitant loss of the immune checkpoint molecules MEF2C and IRAK3 that restrain runaway inflammation 75–77 .…”

“… f, Expression of established microglial activation 67–74 and inflammation checkpoint 75–77 molecules. Violin plots are centered around the median, with their shape representing cell distribution (*** P < 0.001, **** P < 0.00001, MAST).…”

Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation

“…PROS1 is also an agonist for the TAM family of receptor tyrosine kinases, which are regulators of immunity. Given PROS1 is primarily produced by microglia in the brain, this suggests that it may play a role in neuroinflammation 46 . COMP is an extracellular matrix glycoprotein that contains calcium ion binding domains.…”

Tyro3 Contributes to Retinal Ganglion Cell Function, Survival and Dendritic Density in the Mouse Retina

“…Tyro3 is a member of the TAM family, a unique subfamily of receptor tyrosine kinases which also includes Mertk and Axl. The TAM family of receptors play essential roles in phagocytosis, cell survival and immune homeostasis (reviewed in Tondo et al, 2019). The TAM receptors are activated by two closely related ligands, Pros1 and Gas6.…”