Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity

• Published in: Nature immunology Vol. 20; no. 8; pp. 1023 - 1034
• Main Authors: Liu, Qingkun, Johnson, Emily M., Lam, Rachel K., Wang, Qian, Bo Ye, Hong, Wilson, Edward N., Minhas, Paras S., Liu, Ling, Swarovski, Michelle S., Tran, Stephanie, Wang, Jing, Mehta, Swapnil S., Yang, Xi, Rabinowitz, Joshua D., Yang, Samuel S., Shamloo, Mehrdad, Mueller, Christoph, James, Michelle L., Andreasson, Katrin I.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2019; Nature Publishing Group
• Subjects: 631/250/2503; 631/250/2504; 631/250/2520; 631/250/371; Animals; Antioxidants; Biomedical and Life Sciences; Biomedicine; Brain - cytology; Brain - immunology; CD11b antigen; CD45 antigen; Cell Line; Cytokines; Digestive system; Gastrointestinal tract; Immune response; Immunity, Innate - immunology; Immunogenicity; Immunology; Infectious Diseases; Inflammation; Inflammation - pathology; Innate immunity; Intestinal Mucosa - cytology; Intestinal Mucosa - immunology; Intestine; Ischemia; Lamina propria; Macrophages; Macrophages - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid cells; Neuroimaging; Neutrophils - immunology; Norepinephrine; Patient outcomes; Permeability; RAW 264.7 Cells; Spleen; Stroke (Disease); Stroke - pathology; Translocation; Triggering Receptor Expressed on Myeloid Cells-1 - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-019-0421-2

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. Cerebral ischemia activates innate immune responses in injured brain lesions. Andreasson and colleagues show TREM1 is upregulated after stroke and amplifies these proinflammatory responses by peripheral CD11b + myeloid cells in both the ischemic brain and distally in the intestine.