Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity

Liu, Qingkun; Johnson, Emily M.; Lam, Rachel; Wang, Qian; Ye, Hong Bo; Wilson, Edward N.; Minhas, Paras; Liu, Ling; Swarovski, Michelle S.; Tran, Stephanie; Wang, Jing; Mehta, Swapnil; Yang, Xi; Rabinowitz, Joshua D.; Yang, Samuel; Shamloo, Mehrdad; Mueller, Christoph; James, Michelle L.; Andreasson, Katrin I.

doi:10.1038/s41590-019-0421-2

Cited by 125 publications

(100 citation statements)

References 62 publications

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“…Although several mechanisms ( 43 ) (such as the production of reactive oxygen species and the release of metalloproteinases) have been attributed to neutrophils, the existence of neuroprotective N2 neutrophils has also been reported ( 44 ). A recent study in mice identified the triggering receptor expressed on myeloid cells (TREM)-1 as an interesting target for pharmacotherapies aimed at reducing the pro-inflammatory response of peripheral and intestinal myeloid cells after AIS ( 45 ).…”

Section: Pathophysiologymentioning

confidence: 99%

“…TREM1 is a potent enhancer of innate immune responses, it acts by synergizing with classical PRRs, thus inducing the production of proinflammatory cytokines and chemokines, including IL-8, monocyte chemoattractant protein-1 (MCP-1), MCP-3 and macrophage inflammatory (MIP-1α), and inhibition of IL-10 ( 45 ). Furthermore, neurotoxic mechanisms activate the release of pro-inflammatory cytokines such as interleukin-21 from cluster of differentiation (CD)-4 + T cells within 24 h after AIS ( 46 ) and IL-17 from γδT-cells ( 47 ).…”

Section: Pathophysiologymentioning

confidence: 99%

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Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

et al. 2020

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The microbiota-gut-brain axis is considered a central regulator of the immune system after acute ischemic stroke (AIS), with a potential role in determining outcome. Several pathways are involved in the evolution of gut microbiota dysbiosis after AIS. Brain-gut and gut-brain signaling pathways involve bidirectional communication between the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, the enteric nervous system, and the immune cells of the gut. Alterations in gut microbiome can be a risk factor and may also lead to AIS. Both risk factors for AIS and gut-microbiome composition are influenced by similar factors, including diabetes, hypertension, hyperlipidemia, obesity, and vascular dysfunction. Furthermore, the systemic inflammatory response after AIS may yield liver, renal, respiratory, gastrointestinal, and cardiovascular impairment, including the multiple organ dysfunction syndrome. This review focus on biochemical, immunological, and neuroanatomical modulation of gut microbiota and its possible systemic harmful effects after AIS, as well as the role of ischemic stroke on microbiota composition. Finally, we highlight the role of gut microbiota as a potential novel therapeutic target in acute ischemic stroke.

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Section: Pathophysiologymentioning

confidence: 99%

Section: Pathophysiologymentioning

confidence: 99%

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

et al. 2020

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“…A reduced diversity of microbiota species and an overgrowth of bacteria are the main features of post-stroke microbiota dysbiosis, which polarizes immune cells both in gut and brain to adopt a pro-inflammatory phenotype, and this may influence the stroke outcome (43). The leaky gut barrier caused by a stroke also leads to the translocation microbiota and metabolites to trigger neuroinflammation and a peripheral immune response (44). Accumulating evidence suggest that altering the gut microbiota composition can shape the local immune environment in the brain in favor of neurogenesis and axon growth after stroke because lymphocytes have been shown to migrate from gut to brain after stroke: Gut-derived CD4 + T cells migrate to meninges and control the balance between M1 and M2 microglia/macrophage after ischemic injury (45).…”

Section: Gut Microbiota As Potential Regulators Of Neural Repairmentioning

confidence: 99%

Communications Between Peripheral and the Brain-Resident Immune System in Neuronal Regeneration After Stroke

et al. 2020

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Cerebral ischemia may cause irreversible neural network damage and result in functional deficits. Targeting neuronal repair after stroke potentiates the formation of new connections, which can be translated into a better functional outcome. Innate and adaptive immune responses in the brain and the periphery triggered by ischemic damage participate in regulating neural repair after a stroke. Immune cells in the blood circulation and gut lymphatic tissues that have been shaped by immune components including gut microbiota and metabolites can infiltrate the ischemic brain and, once there, influence neuronal regeneration either directly or by modulating the properties of brain-resident immune cells. Immune-related signalings and metabolites from the gut microbiota can also directly alter the phenotypes of resident immune cells to promote neuronal regeneration. In this review, we discuss several potential mechanisms through which peripheral and brain-resident immune components can cooperate to promote first the resolution of neuroinflammation and subsequently to improved neural regeneration and a better functional recovery. We propose that new insights into discovery of regulators targeting pro-regenerative process in this complex neuro-immune network may lead to novel strategies for neuronal regeneration.

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“…Remarkably, novel studies unraveled that in experimental ischemia/stroke, a dramatic up-regulation of TREM-1 occurs firstly in the gut and subsequently in the CNS. This is dependent on the adrenergic nervous system, providing a link between CNS disease, systemic inflammation, and gut barrier dysfunction [62,63]. In detail, in experimental stroke, TREM-1 is up-regulated in myeloid cells within the spleen and intestine, from where it reaches the brain to magnify stroke injury [63].…”

Section: Role Of Trems In Neurodegenerative Disordersmentioning

confidence: 99%

“…This is dependent on the adrenergic nervous system, providing a link between CNS disease, systemic inflammation, and gut barrier dysfunction [62,63]. In detail, in experimental stroke, TREM-1 is up-regulated in myeloid cells within the spleen and intestine, from where it reaches the brain to magnify stroke injury [63]. Within the lamina propria, noradrenergic-dependent increases in gut permeability occur, which contribute to inducing TREM-1 on activated macrophages, further increasing epithelial permeability, facilitating bacterial translocation within the CNS and exacerbating neurological damage [62,63].…”

Section: Role Of Trems In Neurodegenerative Disordersmentioning

confidence: 99%

TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders

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Biagioni

Busceti

et al. 2019

Cells

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Alterations in Triggering Receptors Expressed on Myeloid cells (TREM-1/2) are bound to a variety of infectious, sterile inflammatory, and degenerative conditions, ranging from inflammatory bowel disease (IBD) to neurodegenerative disorders. TREMs are emerging as key players in pivotal mechanisms often concurring in IBD and neurodegeneration, namely microbiota dysbiosis, leaky gut, and inflammation. In conditions of dysbiosis, compounds released by intestinal bacteria activate TREMs on macrophages, leading to an exuberant pro-inflammatory reaction up to damage in the gut barrier. In turn, TREM-positive activated macrophages along with inflammatory mediators may reach the brain through the blood, glymphatic system, circumventricular organs, or the vagus nerve via the microbiota-gut-brain axis. This leads to a systemic inflammatory response which, in turn, impairs the blood-brain barrier, while promoting further TREM-dependent neuroinflammation and, ultimately, neural injury. Nonetheless, controversial results still exist on the role of TREM-2 compared with TREM-1, depending on disease specificity, stage, and degree of inflammation. Therefore, the present review aimed to provide an update on the role of TREMs in the pathophysiology of IBD and neurodegeneration. The evidence here discussed the highlights of the potential role of TREMs, especially TREM-1, in bridging inflammatory processes in intestinal and neurodegenerative disorders.

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Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity

Cited by 125 publications

References 62 publications

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

Communications Between Peripheral and the Brain-Resident Immune System in Neuronal Regeneration After Stroke

TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders

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