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 Reprints and permissions information is available at www.nature.com/reprints.

The inflammatory prostaglandin E2 (PGE 2 ) EP2 receptor is a master suppressor of beneficial microglial function, and myeloid EP2 signaling ablation reduces pathology in models of inflammatory neurodegeneration. Here, we investigated the role of PGE 2 EP2 signaling in a model of stroke in which the initial cerebral ischemic event is followed by an extended poststroke inflammatory response. Myeloid lineage cell-specific EP2 knockdown in Cd11bCre;EP2 lox/lox mice attenuated brain infiltration of Cd11b + CD45 hi macrophages and CD45 + Ly6G hi neutrophils, indicating that inflammatory EP2 signaling participates in the poststroke immune response. Inducible global deletion of the EP2 receptor in adult ROSA26-CreER T2 (ROSACreER);EP2 lox/lox mice also reduced brain myeloid cell trafficking but additionally reduced stroke severity, suggesting that nonimmune EP2 receptor-expressing cell types contribute to cerebral injury. EP2 receptor expression was highly induced in neurons in the ischemic hemisphere, and postnatal deletion of the neuronal EP2 receptor in Thy1Cre;EP2 lox/lox mice reduced cerebral ischemic injury. These findings diverge from previous studies of congenitally null EP2 receptor mice where a global deletion increases cerebral ischemic injury. Moreover, ROSACreER;EP2 lox/lox mice, unlike EP2 −/− mice, exhibited normal learning and memory, suggesting a confounding effect from congenital EP2 receptor deletion. Taken together with a precedent that inhibition of EP2 signaling is protective in inflammatory neurodegeneration, these data lend support to translational approaches targeting the EP2 receptor to reduce inflammation and neuronal injury that occur after stroke. PGE 2 | stroke | conditional knockout T he COX-1 and inducible COX-2 catalyze the first committed step in PGE 2 synthesis and function physiologically in the central nervous system to regulate synaptic plasticity, neurovascular coupling, and glial homeostasis. Of the five prostanoids downstream of COX-including PGE 2 , PGD 2 , PGF 2 α, prostacyclin, and thromboxane-PGE 2 has emerged as a unique modulator of disease-promoting neuronal and inflammatory processes. In pathologic contexts, induction of COX-2 in neurons and glia leads to generation of PGE 2 that signals through four G protein coupled receptors, EP1-EP4. In vivo studies of the EP receptor function using genetic knockout models have highlighted EP receptorspecific effects in a broad range of neurological disease models. For example, whereas the EP1 receptor elicits neurotoxic effects in models of cerebral ischemia (1), the EP4 receptor conversely mediates neuroprotective, vasodilatory, and antiinflammatory effects (2, 3). In models of familial Alzheimer's disease (AD), ablation of EP2 or EP3 receptors blunts inflammatory responses, amyloid accumulation, and loss of synaptic proteins (4-7), whereas deletion of microglial EP4 elicits the opposite (8). Thus, genetic studies demonstrate beneficial as well as detrimental PGE 2 EP signaling cascades that operate in receptor-specific ways.The PGE ...

BackgroundQuantifying morphologic changes is critical to our understanding of the pathophysiology of the lung. Mean linear intercept (MLI) measures are important in the assessment of clinically relevant pathology, such as emphysema. However, qualitative measures are prone to error and bias, while quantitative methods such as mean linear intercept (MLI) are manually time consuming. Furthermore, a fully automated, reliable method of assessment is nontrivial and resource-intensive.MethodsWe propose a semi-automated method to quantify MLI that does not require specialized computer knowledge and uses a free, open-source image-processor (Fiji). We tested the method with a computer-generated, idealized dataset, derived an MLI usage guide, and successfully applied this method to a murine model of particulate matter (PM) exposure. Fields of randomly placed, uniform-radius circles were analyzed. Optimal numbers of chords to assess based on MLI were found via receiver-operator-characteristic (ROC)-area under the curve (AUC) analysis. Intraclass correlation coefficient (ICC) measured reliability.ResultsWe demonstrate high accuracy (AUCROC > 0.8 for MLIactual > 63.83 pixels) and excellent reliability (ICC = 0.9998, p < 0.0001). We provide a guide to optimize the number of chords to sample based on MLI. Processing time was 0.03 s/image. We showed elevated MLI in PM-exposed mice compared to PBS-exposed controls. We have also provided the macros that were used and have made an ImageJ plugin available free for academic research use at https://med.nyu.edu/nolanlab.ConclusionsOur semi-automated method is reliable, equally fast as fully automated methods, and uses free, open-source software. Additionally, we quantified the optimal number of chords that should be measured per lung field.Electronic supplementary materialThe online version of this article (10.1186/s12890-019-0915-6) contains supplementary material, which is available to authorized users.

IntroductionBiomarkers of metabolic syndrome expressed soon after World Trade Center (WTC) exposure predict development of WTC Lung Injury (WTC-LI). The metabolome remains an untapped resource with potential to comprehensively characterise many aspects of WTC-LI. This case–control study identified a clinically relevant, robust subset of metabolic contributors of WTC-LI through comprehensive high-dimensional metabolic profiling and integration of machine learning techniques.MethodsNever-smoking, male, WTC-exposed firefighters with normal pre-9/11 lung function were segregated by post-9/11 lung function. Cases of WTC-LI (forced expiratory volume in 1s

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