Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity

Qingkun Liu, Emily M. Johnson, Rachel K. Lam, Qian Wang, Hong Bo Ye, Edward N. Wilson, Paras S. Minhas, Ling Liu, Michelle S. Swarovski, Stephanie Tran, Jing Wang, Swapnil S. Mehta, Xi Yang, Joshua D. Rabinowitz, Samuel S. Yang, Mehrdad Shamloo, Christoph Mueller, Michelle L. James, Katrin I. Andreasson

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1023-1034
Number of pages12
JournalNature Immunology
Volume20
Issue number8
DOIs
StatePublished - Aug 1 2019

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Liu, Q., Johnson, E. M., Lam, R. K., Wang, Q., Bo Ye, H., Wilson, E. N., Minhas, P. S., Liu, L., Swarovski, M. S., Tran, S., Wang, J., Mehta, S. S., Yang, X., Rabinowitz, J. D., Yang, S. S., Shamloo, M., Mueller, C., James, M. L., & Andreasson, K. I. (2019). Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity. Nature Immunology, 20(8), 1023-1034. https://doi.org/10.1038/s41590-019-0421-2