Myeloid cells as therapeutic targets in neuroinflammation after stroke: Specific roles of neutrophils and neutrophil–platelet interactions

García‐Culebras, Alicia; Durán-Laforet, Violeta; Peña‐Martínez, Carolina; Ballesteros, Iván; Pradillo, Jesús M.; Díaz-Guzmán, Jaime; Moro, Marı́a A.

doi:10.1177/0271678x18795789

Cited by 94 publications

(81 citation statements)

References 174 publications

(225 reference statements)

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“…55 Proinflammatory cytokines released by necrotic cells induce subsequent neutrophil infiltration to ischemic tissue. 56 We found that inflammatory cytokine mRNA expression of IL-1α, IL-1β, IL-6, IL-10, TNF-α, and TGF-β both in vivo and in vitro, and infiltration of neutrophils in vivo did not change with MRS2578 treatment.…”

Section: Fifth Mrs2578 Treatment Exacerbated the Results Of Mnss Andmentioning

confidence: 71%

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P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

et al. 2020

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Introduction Clearance of damaged cells and debris is beneficial for the functional recovery after ischemic brain injury. However, the specific phagocytic receptor that mediates microglial phagocytosis after ischemic stroke is unknown. Aim To investigate whether P2Y6 receptor‐mediated microglial phagocytosis is beneficial for the debris clearance and functional recovery after ischemic stroke. Results The expression of the P2Y6 receptor in microglia increased within 3 days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function as measured by modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL‐1α, IL‐1β, IL‐6, IL‐10, TNF‐α, TGF‐β, and MPO after ischemic stroke. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in the ischemic mouse brain, which suggested that myosin light chain kinase was involved in P2Y6 receptor‐mediated phagocytosis. Conclusion Our results indicate that P2Y6 receptor‐mediated microglial phagocytosis plays a beneficial role during the acute stage of ischemic stroke, which can be a therapeutic target for ischemic stroke.

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Section: Fifth Mrs2578 Treatment Exacerbated the Results Of Mnss Andmentioning

confidence: 71%

“…In response to brain injury, microglia promptly acquire properties of reactive species generation, antigen presentation, phagocytosis, and the production of inflammatory mediators including IL‐1, TNF‐α, and IL‐6 . Proinflammatory cytokines released by necrotic cells induce subsequent neutrophil infiltration to ischemic tissue …”

Section: Discussionmentioning

confidence: 99%

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

et al. 2020

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“…Ischemic stroke induces massive infiltration of blood-borne immune cells into the brain, which are recruited to the site of injury by a variety of chemokines. 3,[6][7][8][9] Monocytes/macrophages are a subset of these immune cells present in high numbers, [10][11][12][13] but their function in the poststroke brain is not well defined. Macrophages have long been known as professional phagocytes due to their high capacity of engulfment.…”

Section: Introductionmentioning

confidence: 99%

Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

et al. 2019

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Aims Blood‐borne monocytes/macrophages infiltrate the brain in massive numbers after ischemic stroke, but their impact on poststroke brain injury and recovery remains elusive. This study examined the transcriptomic changes in monocytes/macrophages after ischemic stroke and the functional implications of these changes, particularly with regards to the contribution of these cells to the phagocytic clearance of dead/dying cells (efferocytosis) in the poststroke brain. Methods We performed whole‐genome RNA sequencing on the monocyte/macrophage population sorted from mouse brain and peripheral blood 5 days after permanent focal cerebral ischemia. In addition, the spatial and temporal profiles of macrophage efferocytosis were examined in vivo by immunohistochemistry 3‐7 days after brain ischemia. Results Robust transcriptomic changes occurred in monocytes/macrophages upon infiltrating the poststroke brain. Functional enrichment analysis revealed a transcriptome of brain macrophages that strongly favored efferocytic activity. A large number of efferocytosis‐related genes were upregulated in brain macrophages, the products of which are essential components involved in various steps of efferocytosis, such as chemotaxis, recognition of dead cells, engulfment, and processing of phagosomes. The efferocytic activity of brain macrophages were verified by immunohistochemistry, wherein Iba1‐labeled microglia/macrophages effectively cleared apoptotic neurons in the infarct during the subacute stage after brain ischemia. We also identified PPARγ and STAT6 as potential upstream regulators that shaped this proefferocytic and inflammation‐resolving transcriptome of macrophages in the poststroke brain. Conclusion Macrophages play a crucial role in the phagocytic clearance of dead neurons after ischemic stroke and promote the resolution of inflammation in the brain. Molecular therapies that enhance macrophage efferocytic capability may be promising treatments for ischemic stroke by facilitating inflammation resolution, brain repair, and recovery of neurological functions.

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“…19 The release of cytokines, chemokines, cellular adhesion molecules (CAMs), and matrix metalloproteinases (MMPs) by damaged neurons and auxiliary cells, such as microglia, astrocytes, and neutrophils, amplifies the neuroinflammatory cascade during the subacute phase of ischemic stroke and TBI. 4,16,19,20 Upregulation of MMPs, in particular, exacerbates localized inflammatory responses by increasing BBB permeability, thereby permitting peripheral leukocytes to infiltrate the injured brain. 19,20 Additionally, CAMs facilitate leukocyte adherence to cerebral vasculature, allowing further recruitment of cells to the injured area.…”

Section: Acute Inflammation In Stroke and Tbimentioning

confidence: 99%

“…4,16,19,20 Upregulation of MMPs, in particular, exacerbates localized inflammatory responses by increasing BBB permeability, thereby permitting peripheral leukocytes to infiltrate the injured brain. 19,20 Additionally, CAMs facilitate leukocyte adherence to cerebral vasculature, allowing further recruitment of cells to the injured area. Activated microglia and astrocytes prolong inflammation into the chronic phase via continued secretion of cytokines, chemokines, and CAMs, thus attracting more peripheral macrophages and neutrophils through the leaky BBB and other novel deleterious microglial and downstream signaling pathways.…”

Section: Acute Inflammation In Stroke and Tbimentioning

confidence: 99%

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

et al. 2020

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Acquired brain injury (ABI) entails any injury that disrupts neuronal activity and is not degenerative, hereditary, congenital, or induced by birth trauma. Traditional examples of ABI include not only stroke and traumatic brain injury (TBI), but also near drowning, aneurysm, tumor, meningitis and other infections involving the brain, and injuries resulting from lack of oxygen supply to the brain, such as those seen in myocardial infarction. ABI may involve a structural insult, changes to metabolic activity, or disruption to neuronal capabilities.While progressive loss of brain cells and debilitating motor and cognitive deficits play a role in all these disorders, stroke and TBI overlap particularly closely in pathology and impose an immense burden on the American and global populations. AbstractIschemic stroke and traumatic brain injury (TBI) comprise two particularly prevalent and costly examples of acquired brain injury (ABI). Following stroke or TBI, primary cell death and secondary cell death closely model disease progression and worsen outcomes. Mounting evidence indicates that long-term neuroinflammation extensively exacerbates the secondary deterioration of brain structure and function. Due to their immunomodulatory and regenerative properties, mesenchymal stem cell transplants have emerged as a promising approach to treating this facet of stroke and TBI pathology. In this review, we summarize the classification of cell death in ABI and discuss the prominent role of inflammation. We then consider the efficacy of bone marrow-derived mesenchymal stem/stromal cell (BM-MSC) transplantation as a therapy for these injuries. Finally, we examine recent laboratory and clinical studies utilizing transplanted BM-MSCs as antiinflammatory and neurorestorative treatments for stroke and TBI. Clinical trials of BM-MSC transplants for stroke and TBI support their promising protective and regenerative properties. Future research is needed to allow for better comparison among trials and to elaborate on the emerging area of cell-based combination treatments. K E Y W O R D Sbone marrow-derived mesenchymal stem cells, clinical trials, inflammation, ischemic stroke, preclinical studies, traumatic brain injury

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Myeloid cells as therapeutic targets in neuroinflammation after stroke: Specific roles of neutrophils and neutrophil–platelet interactions

Cited by 94 publications

References 174 publications

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

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