Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity
Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity
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DOI：
10.1038/s41590-019-0421-2
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发表时间：
2019-08-01
影响因子：
30.5
通讯作者：
Andreasson, Katrin I.
中科院分区：
文献类型：
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作者：
Liu, Qingkun;Johnson, Emily M.;Andreasson, Katrin I.
中风是一个多阶段的过程，其中最初的脑缺血随后是对缺血脑成分的免疫反应引起的继发性损伤。在这里，我们证明了外周CD11b（+）CD45（+）髓样细胞通过激活髓样细胞上表达的触发受体1（TREM1）放大中风损伤，TREM1是促炎性先天免疫反应的放大器。TREM1在中风后数小时内在外周向缺血脑运输的CD11b（+）CD45（+）细胞中诱导。TREM1抑制通过保护性抗氧化剂和抗炎机制在遗传上或非遗传上改善结果。使用放射性标记的识别TREM1的抗体的正电子断层扫描成像揭示了脾脏中的TREM1表达升高，并且出乎意料地，在肠中。在固有层中，肠道通透性的去甲肾上腺素能依赖性增加诱导了炎症性Ly6C（+）MHCII（+）巨噬细胞上的TREM1，进一步增加了上皮通透性，促进了细菌穿过肠道屏障的移位。因此，中风后，外周TREM1诱导放大了对脑源性和脑源性免疫原性组分的促炎反应。至关重要的是，靶向这种特异性先天免疫途径可以减少脑损伤。
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.