RESUMO
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.
Assuntos
Encéfalo/imunologia , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Acidente Vascular Cerebral/patologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Animais , Encéfalo/citologia , Linhagem Celular , Imunidade Inata/imunologia , Inflamação/patologia , Mucosa Intestinal/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7RESUMO
Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-ß42 oligomer-induced bioenergetic changes, suggesting that amyloid-ß42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.
Assuntos
Envelhecimento , Doença de Alzheimer , Modelos Animais de Doenças , Metabolismo Energético , Microglia , Receptor Gatilho 1 Expresso em Células Mieloides , Animais , Camundongos , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Cognição/fisiologia , Metabolismo Energético/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genéticaRESUMO
BACKGROUND: CyberKnife stereotactic radiosurgery (SRS) for trigeminal neuralgia (TGN) administers nonisometric, conformational high-dose radiation to the trigeminal nerve with risk of subsequent hypoesthesia. METHODS: We performed a retrospective, single-institution review of 66 patients with TGN treated with CyberKnife SRS to compare outcomes from 2 distinct treatment periods: standard dosing (n = 38) and reduced dosing (n = 28). Standard and reduced dosing permitted a maximum brainstem dose of 45 Gy and 25 Gy, respectively, each with a prescription dose of 60 Gy. Primary and secondary outcomes were Barrow Neurologic Institute pain and numbness scores. Maximum brainstem dose, prepontine nerve length, and treatment history were recorded for their predictive contributions by logistic regression. RESULTS: After matching, patients in the standard dosing and reduced dosing groups were followed for a median of 25 months and 19.5 months, respectively. Mean trigeminal nerve length was 8.55 mm in the standard dosing group and 9.46 mm in the reduced dosing group. Baseline rates of poorly controlled pain were 97% and 88%, respectively, which improved to 23.4% and 8.3%, respectively (P < 0.001 for both). The baseline rates of bothersome numbness were null in both groups, and increased to 25% in the standard group (P = 0.006) and to 21% in the reduced group (P = 0.07). Regression analyses suggested that reduced brainstem exposure (P = 0.01), as well as a longer trigeminal nerve (P = 0.01), were predictive of durable pain control. CONCLUSIONS: These outcomes demonstrate that a lower maximum brainstem dose can provide excellent pain control without affecting facial numbness. Longer nerves may achieve better long-term outcomes and help optimize individual plans.
Assuntos
Tronco Encefálico/efeitos da radiação , Radiocirurgia , Neuralgia do Trigêmeo/cirurgia , Idoso , Antropometria , Estudos de Casos e Controles , Relação Dose-Resposta à Radiação , Feminino , Humanos , Hipestesia/etiologia , Masculino , Pessoa de Meia-Idade , Parestesia/etiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Lesões por Radiação/prevenção & controle , Radiometria , Estudos Retrospectivos , Nervo Trigêmeo/patologia , Doenças do Nervo Trigêmeo/etiologiaRESUMO
UNLABELLED: Pediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements. In this study, we describe the somatic landscape of pediatric Ewing sarcoma. These tumors are among the most genetically normal cancers characterized to date, with only EWS-ETS rearrangements identified in the majority of tumors. STAG2 loss, however, is present in more than 15% of Ewing sarcoma tumors; occurs by point mutation, rearrangement, and likely nongenetic mechanisms; and is associated with disease dissemination. Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways, highlighting the need for new therapeutic approaches to target EWS-ETS fusions in this disease. SIGNIFICANCE: We performed next-generation sequencing of Ewing sarcoma, a pediatric cancer involving bone, characterized by expression of EWS-ETS fusions. We found remarkably few mutations. However, we discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing sarcoma.