Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity. Author Qingkun Liu, Emily Johnson, Rachel Lam, Qian Wang, Hong Ye, Edward Wilson, Paras Minhas, Ling Liu, Michelle Swarovski, Stephanie Tran, Jing Wang, Swapnil Mehta, Xi Yang, Joshua Rabinowitz, Samuel Yang, Mehrdad Shamloo, Christoph Mueller, Michelle James, Katrin Andreasson Publication Year 2019 Type Journal Article 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 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. Keywords Animals, Mice, Cell Line, Mice, Inbred C57BL, Brain, Mice, Knockout, Immunity, Innate, Inflammation, Macrophages, Intestinal Mucosa, Neutrophils, RAW 264.7 Cells, Stroke, Triggering Receptor Expressed on Myeloid Cells-1 Journal Nat Immunol Volume 20 Issue 8 Pages 1023-1034 Date Published 2019 Aug ISSN Number 1529-2916 DOI 10.1038/s41590-019-0421-2 Alternate Journal Nat Immunol PMCID PMC6778967 PMID 31263278 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML