Multiple sclerosis (MS) is an autoimmune disease characterized by the destruction of myelin in the central nervous system (CNS) and secondary neurodegeneration. Currently, it is believed that an MS episode is initiated by autoreactive T-cells and then further exacerbated by an inflammatory milieu created by the resident and peripheral myeloid cells. After an MS inflammatory episode, inflammation is resolved, but the mechanisms that promote the return to homeostasis remain elusive. Key events involved in the resolution of inflammation are the removal of cellular debris and the termination of the inflammatory program. Our long-term goal is to shed light on the mechanisms that control the resolution of inflammation in the CNS, which will facilitate the development of novel therapeutics for neuroinflammatory disorders such as MS. Low density lipoprotein receptor-related protein-1 (LRP1) is scavenger receptor that is highly expressed on myeloid cells, including the CNS-resident microglia. LRP1 promotes the phagocytosis of debris such as degraded myelin and dying cells, which are present during MS inflammatory episodes. The foundation of this proposal is our discovery that LRP1 also functions as an inhibitor of inflammation, as cells lacking LRP1 display increased and sustained inflammatory responses following stimulation. Furthermore, mice with the deletion of LRP1 in myeloid cells have increased disease severity in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Functions of LRP1 in debris clearance and inhibition of inflammation put this receptor at the center stage as a potential regulator of the resolution of inflammation in MS. Our hypothesis is that LRP1 in myeloid cells limits tissue damage during MS by enhancing the removal of cellular debris and by shutting down the inflammatory response. Guided by strong preliminary evidence, this hypothesis will be addressed by pursuing three specific aims: 1) Test if LRP1 inhibits inflammation by promoting phagocytosis of tissue debris. 2) Test the contribution of myeloid LRP1 to the phagocytosis of degenerated myelin in vivo. 3) Test the functional role of LRP1 during EAE, using mouse model systems with the conditional deletion of LRP1 in microglia or myeloid cells. Under the first aim, we will study the cross-talk between LRP1 mediated phagocytosis and inflammation using primary cultures of myeloid cells. In the second aim, we will use two-photon live imaging of LRP1 mediated myelin phagocytosis. In the final aim, we will study the contribution of microglial and inflammatory macrophage LRP1 during EAE pathology. Our approach is innovative because we will investigate the function of a scavenger receptor, LRP1, during the return to homeostasis after neuroinflammation using new animal models combined with the state of the art live imaging in the CNS. Our proposal is significant because these studies will provide the basis for understanding the function of LRP1 in MS with the ultimate goal of developing novel anti-inflammatory treatments for MS patients.
Multiple sclerosis (MS) is a devastating neurodegenerative disease, characterized by the destruction of the myelin sheath, necessary for nerve impulse propagation, by the immune system. This proposal is focused on a cellular protein, LRP1, which we show is important in the inflammatory response and which delays the progression of disease symptoms in an animal model of MS. We aim to understand the mechanisms by which LRP1 inhibits inflammation during MS, with the potential of discovering alternative options for treatment of MS patients.
| Uchiyama, Robin; Kupkova, Kristyna; Shetty, Savera J et al. (2018) Histone H3 lysine 4 methylation signature associated with human undernutrition. Proc Natl Acad Sci U S A 115:E11264-E11273 |
| Seki, Scott M; Gaultier, Alban (2017) Exploring Non-Metabolic Functions of Glycolytic Enzymes in Immunity. Front Immunol 8:1549 |
| Seki, Scott M; Stevenson, Max; Rosen, Abagail M et al. (2017) Lineage-Specific Metabolic Properties and Vulnerabilities of T Cells in the Demyelinating Central Nervous System. J Immunol 198:4607-4617 |
| Fernandez-Castaneda, Anthony; Gaultier, Alban (2016) Adult oligodendrocyte progenitor cells - Multifaceted regulators of the CNS in health and disease. Brain Behav Immun 57:1-7 |
| Chuang, Tzu-Ying; Guo, Yong; Seki, Scott M et al. (2016) LRP1 expression in microglia is protective during CNS autoimmunity. Acta Neuropathol Commun 4:68 |
