Microglial LRP1 modulates neuroinflammation via control of the NF-κB pathway in autoimmunity
Chuang, Tzu Ying, Experimental Pathology - Graduate School of Arts and Sciences, University of Virginia
Gaultier, Alban, Department of Neuroscience, University of Virginia
Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS), characterized by immune cell infiltration and inflammation. While T cells are known contributors to MS pathology, the precise function of CNS resident and peripheral infiltrating myeloid cells is more controversial. In this work I delineate the myeloid cell function of LRP1, a scavenger receptor crucial for myelin clearance and the inflammatory response, in the context of MS. I find that LRP1 expression is increased in the MS lesion in comparison to the surrounding healthy tissue. Using two genetic mouse models, I show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. I further demonstrate that this increase in EAE disease severity is not due to haplodeficiency of the Cx3cr1 locus. Furthermore, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNFα. I also show that LRP1 inhibits NF-κB activation in myeloid cells via a MyD88 dependent mechanism. Together, my data suggests that LRP1 functions in microglia to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in MS. I also initiated studies exploring the role of LRP1 as a phagocytic receptor of myelin during MS using a combination of in vitro and in vivo models. This work will provide a foundation for future studies regarding the role of LRP1 in mediating the crosstalk between phagocytosis and inflammation.
PHD (Doctor of Philosophy)
Multiple Sclerosis, NF-κB, LRP1
UVA Medical Scientist Training Program