Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity

Nat Immunol. 2019 Aug;20(8):1023-1034. doi: 10.1038/s41590-019-0421-2. Epub 2019 Jul 1.


Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11b+CD45+ myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11b+CD45+ cells trafficking to ischemic brain. TREM1 inhibition genetically or pharmacologically improved outcome via protective antioxidant and anti-inflammatory mechanisms. Positron electron tomography imaging using radiolabeled antibody recognizing TREM1 revealed elevated TREM1 expression in spleen and, unexpectedly, in intestine. In the lamina propria, noradrenergic-dependent increases in gut permeability induced TREM1 on inflammatory Ly6C+MHCII+ macrophages, further increasing epithelial permeability and facilitating bacterial translocation across the gut barrier. Thus, following stroke, peripheral TREM1 induction amplifies proinflammatory responses to both brain-derived and intestinal-derived immunogenic components. Critically, targeting this specific innate immune pathway reduces cerebral injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / immunology*
  • Cell Line
  • Immunity, Innate / immunology
  • Inflammation / pathology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology*
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / immunology*
  • RAW 264.7 Cells
  • Stroke / pathology*
  • Triggering Receptor Expressed on Myeloid Cells-1 / metabolism*


  • TREM1 protein, mouse
  • Triggering Receptor Expressed on Myeloid Cells-1