Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity

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; Müller, Christoph; James, Michelle L.; Andreasson, Katrin I. (2019). Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity. Nature immunology, 20(8), pp. 1023-1034. Nature Publishing Group 10.1038/s41590-019-0421-2

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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.

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