Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity.
Qingkun LiuEmily M JohnsonRachel K LamQian WangHong Bo YeEdward N WilsonParas S MinhasLing LiuMichelle S SwarovskiStephanie TranJing WangSwapnil S MehtaXi YangJoshua D RabinowitzSamuel S YangMehrdad ShamlooChristoph MüllerMichelle L JamesKatrin I AndreassonPublished in: Nature immunology (2019)
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.
Keyphrases
- cerebral ischemia
- subarachnoid hemorrhage
- immune response
- induced apoptosis
- brain injury
- blood brain barrier
- cell cycle arrest
- atrial fibrillation
- resting state
- dendritic cells
- white matter
- oxidative stress
- anti inflammatory
- diabetic rats
- acute myeloid leukemia
- endothelial cells
- poor prognosis
- functional connectivity
- innate immune
- toll like receptor
- endoplasmic reticulum stress
- high resolution
- nk cells