Microglial LRP1 modulates neuroinflammation via control of the NF-κB pathway in autoimmunity

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.