Leukocyte infiltration into spinal cord of EAE mice is attenuated by removal of endothelial leptin signaling

Brain Behav Immun. 2014 Aug;40:61-73. doi: 10.1016/j.bbi.2014.02.003. Epub 2014 Feb 24.

Abstract

Leptin, a pleiotropic adipokine, crosses the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) from the periphery and facilitates experimental autoimmune encephalomyelitis (EAE). EAE induces dynamic changes of leptin receptors in enriched brain and spinal cord microvessels, leading to further questions about the potential roles of endothelial leptin signaling in EAE progression. In endothelial leptin receptor specific knockout (ELKO) mice, there were lower EAE behavioral scores in the early phase of the disorder, better preserved BSCB function shown by reduced uptake of sodium fluorescein and leukocyte infiltration into the spinal cord. Flow cytometry showed that the ELKO mutation decreased the number of CD3 and CD45 cells in the spinal cord, although immune cell profiles in peripheral organs were unchanged. Not only were CD4(+) and CD8(+) T lymphocytes reduced, there were also lower numbers of CD11b(+)Gr1(+) granulocytes in the spinal cord of ELKO mice. In enriched microvessels from the spinal cord of the ELKO mice, the decreased expression of mRNAs for a few tight junction proteins was less pronounced in ELKO than WT mice, as was the elevation of mRNA for CCL5, CXCL9, IFN-γ, and TNF-α. Altogether, ELKO mice show reduced inflammation at the level of the BSCB, less leukocyte infiltration, and better preserved tight junction protein expression and BBB function than WT mice after EAE. Although leptin concentrations were high in ELKO mice and microvascular leptin receptors show an initial elevation before inhibition during the course of EAE, removal of leptin signaling helped to reduce disease burden. We conclude that endothelial leptin signaling exacerbates BBB dysfunction to worsen EAE.

Keywords: Autoimmunity; Blood–spinal cord barrier; EAE; Endothelia; Leptin receptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / blood supply
  • Brain / immunology
  • Cytokines / immunology
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Endothelial Cells / metabolism
  • Female
  • Leptin / blood*
  • Leukocytes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger / metabolism
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism*
  • Severity of Illness Index
  • Signal Transduction
  • Spinal Cord / blood supply
  • Spinal Cord / immunology*
  • Tight Junctions / immunology

Substances

  • Cytokines
  • Leptin
  • RNA, Messenger
  • Receptors, Leptin