Role of polymorphonuclear neutrophils in the reperfused ischemic brain: insights from cell-type-specific immunodepletion and fluorescence microscopy studies

Hermann, Dirk M.; Kleinschnitz, Christoph; Gunzer, Matthias

doi:10.1177/1756286418798607

Cited by 14 publications

(18 citation statements)

References 53 publications

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“…Neutrophils are attracted to the injured brain after acute stroke [10,23,30,31,50,51]. Thereby, neutrophils adhere to venules and migrate through the vessel wall to reach perivascular spaces [17].…”

Section: Discussionmentioning

confidence: 99%

Microglial cell loss after ischemic stroke favors brain neutrophil accumulation

et al. 2018

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Stroke attracts neutrophils to the injured brain tissue where they can damage the integrity of the blood–brain barrier and exacerbate the lesion. However, the mechanisms involved in neutrophil transmigration, location and accumulation in the ischemic brain are not fully elucidated. Neutrophils can reach the perivascular spaces of brain vessels after crossing the endothelial cell layer and endothelial basal lamina of post-capillary venules, or migrating from the leptomeninges following pial vessel extravasation and/or a suggested translocation from the skull bone marrow. Based on previous observations of microglia phagocytosing neutrophils recruited to the ischemic brain lesion, we hypothesized that microglial cells might control neutrophil accumulation in the injured brain. We studied a model of permanent occlusion of the middle cerebral artery in mice, including microglia- and neutrophil-reporter mice. Using various in vitro and in vivo strategies to impair microglial function or to eliminate microglia by targeting colony stimulating factor 1 receptor (CSF1R), this study demonstrates that microglial phagocytosis of neutrophils has fundamental consequences for the ischemic tissue. We found that reactive microglia engulf neutrophils at the periphery of the ischemic lesion, whereas local microglial cell loss and dystrophy occurring in the ischemic core are associated with the accumulation of neutrophils first in perivascular spaces and later in the parenchyma. Accordingly, microglia depletion by long-term treatment with a CSF1R inhibitor increased the numbers of neutrophils and enlarged the ischemic lesion. Hence, microglial phagocytic function sets a critical line of defense against the vascular and tissue damaging capacity of neutrophils in brain ischemia. Electronic supplementary material The online version of this article (10.1007/s00401-018-1954-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Microglial cell loss after ischemic stroke favors brain neutrophil accumulation

et al. 2018

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“…IL‐17R is expressed on both glial cells and BMECs and up‐regulated after stroke in experimental models 52,62 . By binding with IL‐17R, IL‐17A promotes glia and BMECs to secrete large amounts of CXCL1 52,60,62 to induce neutrophils to infiltrate the cerebral parenchyma and inflict damage in stroke 63,64 . The main manifestations of neutrophils effects include the following: (1) activate MMPs (especially MMP‐2, ‐9) and hydrolyse endothelial cell tight junction proteins (TJs) to destroy the structural integrity of the BBB 65,66 ; and (2) secrete inflammatory cytokines, chemokines and adhesion molecules, and induce the infiltration of CD8 + T cells via CXCL12 65 .…”

Section: Il‐17a Promotes Neutrophil Infiltration In Strokementioning

confidence: 99%

Interleukin‐17 and ischaemic stroke

et al. 2020

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SummaryInterleukin‐17 (IL‐17) is a cytokine family that includes 6 members, IL‐17A through IL‐17F, most of them are reported to have pro‐inflammatory role. Through binding to their receptors (IL‐17Rs), IL‐17 activates the intracellular signalling pathways to play an important role in autoimmune diseases, including rheumatoid arthritis (RA) and multiple sclerosis (MS). Ischaemic stroke is a complex pathophysiological process mainly caused by regional cerebral ischaemia. Inflammatory factors contribute to the physiological process of stroke that leads to poor prognosis. IL‐17 plays a crucial role in promoting inflammatory response and inducing secondary injury in post‐stroke. Though immune cells and inflammatory factors have been reported to be involved in the damage of stroke, the functions of IL‐17 in this process need to be elucidated. This review focuses on the pathological modulation and the mechanism of IL‐17 family in ischaemic stroke and seeking to provide new insights for future therapies.

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“…Like in the retina, ischemia in these organs leads to CD40‐driven upregulation of chemokines and adhesion molecules, promoting leukocyte recruitment and tissue injury 24,51,52 . While the recruitment of leukocyte subsets such as macrophages, microglia, and lymphocytes can play either a detrimental role (impair blood‐brain barrier integrity, aggravate neuron injury, secrete pro‐inflammatory cytokines) or a protective role (phagocytose cell debris, express anti‐inflammatory cytokines and neuroprotectants) after cerebral ischemia, 53 several studies support the deleterious role of infiltrating PMN 54 . Indeed, PMNs can be key mediators of injury after I/R 37,54 and blockade of ICAM‐1 or CXCL1 protects against inflammation and organ injury after I/R 55,56 .…”

Section: Discussionmentioning

confidence: 99%

A cell‐penetrating CD40‐TRAF2,3 blocking peptide diminishes inflammation and neuronal loss after ischemia/reperfusion

Portillo

Hansen

et al. 2021

FASEB j.

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While the administration of anti‐CD154 mAbs in mice validated the CD40‐CD154 pathway as a target against inflammatory disorders, this approach caused thromboembolism in humans (unrelated to CD40 inhibition) and is expected to predispose to opportunistic infections. There is a need for alternative approaches to inhibit CD40 that avoid these complications. CD40 signals through TRAF2,3 and TRAF6‐binding sites. Given that CD40‐TRAF6 is the pathway that stimulates responses key for cell‐mediated immunity against opportunistic pathogens, we examined the effects of pharmacologic inhibition of CD40‐TRAF2,3 signaling. We used a model of ischemia/reperfusion (I/R)‐induced retinopathy, a CD40‐driven inflammatory disorder. Intravitreal administration of a cell‐penetrating CD40‐TRAF2,3 blocking peptide impaired ICAM‐1 upregulation in retinal endothelial cells and CXCL1 upregulation in endothelial and Müller cells. The peptide reduced leukocyte infiltration, upregulation of NOS2/COX‐2/TNF‐α/IL‐1β, and ameliorated neuronal loss, effects that mimic those observed after I/R in Cd40−/− mice. While a cell‐penetrating CD40‐TRAF6 blocking peptide also diminished I/R‐induced inflammation, this peptide (but not the CD40‐TRAF2,3 blocking peptide) impaired control of the opportunistic pathogen Toxoplasma gondii in the retina. Thus, inhibition of the CD40‐TRAF2,3 pathway is a novel and potent approach to reduce CD40‐induced inflammation, while likely diminishing the risk of opportunistic infections that would otherwise accompany CD40 inhibition.

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Role of polymorphonuclear neutrophils in the reperfused ischemic brain: insights from cell-type-specific immunodepletion and fluorescence microscopy studies

Cited by 14 publications

References 53 publications

Microglial cell loss after ischemic stroke favors brain neutrophil accumulation

Microglial cell loss after ischemic stroke favors brain neutrophil accumulation

Interleukin‐17 and ischaemic stroke

A cell‐penetrating CD40‐TRAF2,3 blocking peptide diminishes inflammation and neuronal loss after ischemia/reperfusion

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