Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity.

TitlePeripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity.
Publication TypeJournal Article
Year of Publication2019
AuthorsLiu, Q, Johnson, EM, Lam, RK, Wang, Q, Ye, HBo, Wilson, EN, Minhas, PS, Liu, L, Swarovski, MS, Tran, S, Wang, J, Mehta, SS, Yang, X, Rabinowitz, JD, Yang, SS, Shamloo, M, Mueller, C, James, ML, Andreasson, KI
JournalNat Immunol
Volume20
Issue8
Pagination1023-1034
Date Published2019 08
ISSN1529-2916
KeywordsAnimals, Brain, Cell Line, Immunity, Innate, Inflammation, Intestinal Mucosa, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils, RAW 264.7 Cells, Stroke, Triggering Receptor Expressed on Myeloid Cells-1
Abstract

<p>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 CD11bCD45 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 CD11bCD45 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 Ly6CMHCII 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.</p>

DOI10.1038/s41590-019-0421-2
Alternate JournalNat Immunol
PubMed ID31263278
PubMed Central IDPMC6778967
Grant ListR01 NS045727 / NS / NINDS NIH HHS / United States
R01 NS100180 / NS / NINDS NIH HHS / United States
R21 NS087639 / NS / NINDS NIH HHS / United States
RF1 AG053001 / AG / NIA NIH HHS / United States