Talk abstracts
Talk on Thursday 05:00-05:15pm submitted by Calli Bellinger
Microglial MerTK as a key modulator of CNS region-specific inflammation during EAE
Calli Bellinger (Neuroscience Graduate Program), Benjamin Segal (Neurology, The Ohio State University Wexner Medical Center)
Abstract:
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). It is widely believed to be autoimmune in etiology. The type I receptor tyrosine kinase MerTK, expressed by myeloid cells, plays a critical role in clearing apoptotic cells and myelin debris and in modulating inflammatory responses. Genetic variants in Mertk are associated with MS susceptibility, and monocytes from MS patients exhibit reduced MerTK expression and impaired myelin phagocytosis. Experimental autoimmune encephalomyelitis (EAE), an established murine model of MS, is induced by adoptive transfer of encephalitogenic Th17 cells into syngeneic hosts. It typically presents as ascending paralysis, driven by inflammation, demyelination, and axonopathy that is focused in the spinal cord (SC). Our lab previously showed that pharmacologic inhibition of the TAM receptors (Tyro3, Axl and MerTK) at the time of Th17 cell transfer induces a high rate of atypical EAE characterized by initial ataxia followed by hindlimb weakness, accompanied by enhanced neuroinflammation in the hindbrain (HBr). This suggests that TAM signaling regulates the regional localization of autoimmune neuroinflammation. We found that microglia in the HBr express higher basal levels of MerTK compared to those in the SC or forebrain. Moreover, the TAM ligand Gas6 is constitutively present in the CNS, leading us to hypothesize that tonic MerTK signaling in HBr microglia limits inflammatory infiltration. To test this, we generated microglia-specific Mertk knockout mice (Cx3cr1-CreERT2: Mertkfl/fl). When treated with tamoxifen prior to Th17 transfer, these mice presented with atypical EAE at significantly higher rates than controls. In contrast, deletion of Mertk, Axl, or both in hematopoietic myeloid cells (LysM-Cre) had no effect on disease pattern, underscoring the unique role of microglial MerTK in regional immune regulation.
These findings identify microglial MerTK as a key modulator of CNS region-specific inflammation during autoimmune demyelination. Ongoing studies aim to define the underlying molecular mechanisms. By illuminating how microglia shape the topography of MS lesions, this work may inform novel therapeutic strategies that target microglial MerTK signaling to modulate neuroinflammation in MS.
Keywords: Microglia, Neuroimmunology, Multiple Sclerosis