LRP1 expression in microglia is protective during CNS autoimmunity

Tzu Ying Chuang, Yong Guo, Scott M. Seki, Abagail M. Rosen, David M. Johanson, James W. Mandell, Claudia F. Lucchinetti, Alban Gaultier

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis. Supporting its central role in Multiple sclerosis pathology, we find that LRP1 expression is increased in Multiple sclerosis lesions in comparison to the surrounding healthy tissue. Using two genetic mouse models, we show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis, an animal model of Multiple sclerosis. We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus. At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α. We also show that LRP1 functions as a robust inhibitor of NF-kB activation in myeloid cells via a MyD88 dependent pathway, potentially explaining the increase in disease severity observed in mice lacking LRP1 expression in microglia. Taken together, our data suggest that the function of LRP1 in microglia is to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in Multiple sclerosis.

Original languageEnglish (US)
Pages (from-to)68
Number of pages1
JournalActa Neuropathologica Communications
Volume4
Issue number1
DOIs
StatePublished - Jul 11 2016

Keywords

  • Inflammation
  • LRP1
  • Microglia
  • Multiple sclerosis
  • NF-kB

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'LRP1 expression in microglia is protective during CNS autoimmunity'. Together they form a unique fingerprint.

  • Cite this

    Chuang, T. Y., Guo, Y., Seki, S. M., Rosen, A. M., Johanson, D. M., Mandell, J. W., Lucchinetti, C. F., & Gaultier, A. (2016). LRP1 expression in microglia is protective during CNS autoimmunity. Acta Neuropathologica Communications, 4(1), 68. https://doi.org/10.1186/s40478-016-0343-2