Mast Cells Are Early Responders After Hypoxia-Ischemia in Immature Rat Brain

Jin, Yuxuan; Silverman, Ann Judith; Vannucci, Susan J.

doi:10.1161/strokeaha.109.549691

Cited by 127 publications

(113 citation statements)

References 38 publications

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“…A previous study suggested that activated MCs but not microglia were the "first responders" in brain injury [38]. Although other resident cells in the CNS produce TNF-α (most notably microglia [39,40] and endothelial cells [41]), the presence and release of TNF-α from MCs precedes its detection in other cells.…”

Section: Discussionmentioning

confidence: 97%

Induction of Microglial Activation by Mediators Released from Mast Cells

Zhang¹,

Wang²,

Dong³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Microglia are the resident immune cells in the brain and play a pivotal role in immune surveillance in the central nervous system (CNS). Brain mast cells are activated in CNS disorders and induce the release of several mediators. Thus, brain mast cells, rather than microglia, are the “first responders” due to injury. However, the functional aspects of mast cell-microglia interactions remain uninvestigated. Methods: Conditioned medium from activated HMC-1 cells induces microglial activation similar to co-culture of microglia with HMC-1 cells. Primary cultured microglia were examined by flow cytometry analysis and confocal microscopy. TNF- alpha and IL-6 were measured with commercial ELISA kits. Cell signalling was analysed by Western blotting. Results: In the present study, we found that the conditioned medium from activated HMC-1 cells stimulated microglial activation and the subsequent production of the pro-inflammatory factors TNF-α and IL-6. Co-culture of microglia and HMC-1 cells with corticotropin-releasing hormone (CRH) for 24, 48 and 72 hours increased TNF-α and IL-6 production. Antagonists of histamine receptor 1 (H₁R), H₄R, proteinase-activated receptor 2 (PAR2) or Toll-like receptor 4 (TLR4) reduced HMC-1-induced pro-inflammatory factor production and MAPK and PI3K/AKT pathway activation. Conclusions: These results imply that activated mast cells trigger microglial activation. Interactions between mast cells and microglia could constitute a new and unique therapeutic target for CNS inflammation-related diseases.

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Section: Discussionmentioning

confidence: 97%

Induction of Microglial Activation by Mediators Released from Mast Cells

Zhang¹,

Wang²,

Dong³

et al. 2016

Cell Physiol Biochem

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“…8,11 The molecular mechanisms behind such action, however, have remained elusive. Here, we provide mechanistic insight into the processes leading to BBB disruption following reperfusion-induced MC activation.…”

Section: Discussionmentioning

confidence: 99%

Cerebral Mast Cells Mediate Blood-Brain Barrier Disruption in Acute Experimental Ischemic Stroke Through Perivascular Gelatinase Activation

Mattila

Strbian

Saksi

et al. 2011

Stroke

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Background and Purpose-Perivascularly positioned cerebral mast cells (MC) have been shown to participate in acute blood-brain barrier disruption and expansive brain edema following experimental transient cerebral ischemia. However, the underlying molecular mechanisms remain unknown. Because proteolytic gelatinase enzymes, matrix metalloproteinases (MMP)-2 and MMP-9, are thought to have a central role in compromising the integrity of the blood-brain barrier following ischemia, we examined whether cerebral MCs influence gelatinase activity in ischemic cerebral microvasculature. Methods-Rats underwent 60 minutes of middle cerebral artery occlusion followed by 3-hour reperfusion, and were treated with a MC-stabilizing (cromoglycate), or Key Words: mast cells Ⅲ gelatinases Ⅲ blood-brain barrier E xpansive brain edema is a frequent cause of death after large ischemic strokes, 1 as it reduces blood flow in the ischemic penumbra and can lead to herniation of brain structures. Edema is predominantly caused by functional and structural disturbance of the blood-brain barrier (BBB). Proteolytic gelatinase enzymes, most importantly matrix metalloproteinases (MMP)-2 and MMP-9, are considered to be central mediators of ischemic BBB disruption; this is because of their ability to degrade components of microvascular basal lamina, especially collagen type IV, 2-4 and to disrupt tight junction proteins. 5 The mechanisms triggering early activation of gelatinases in ischemic brain remain under active debate. 2,6 Mast cells (MC) are resident inflammatory cells positioned in the outer layers of various tissues (eg, mucosa, epithelia, and vasculature) in mammals, including the central nervous system. 7 We and others have previously shown that MCs have a role in the pathophysiology of ischemic, hypoxic-ischemic, and hemorrhagic brain injury. 8 -11 Both pharmacological inhibition and genetic deficiency of MCs led to a significant reduction in postischemic BBB disruption, cerebral edema, and neutrophil infiltration, 8 presenting MC inhibition as a potential therapeutic avenue to prevent inflammatory damage to the neurovasculature, especially in conjunction with thrombolytics. 9 We envisaged a molecular pathway for ischemic BBB disruption where factors liberated from MCs might fuel gelatinase activation within the targeted neurovascular unit and lead to degradation of the microvascular wall, especially Materials and Methods AnimalsThe in vivo methodology has been described in detail previously. 8 Briefly, adult, male, Wistar rats (Harlan Nederland) and WsRc Ws/Ws rats (Japan SLC, Inc), 290 to 340g, were anesthetized with ketamin hydrochloride (intraperitoneal, 50 mg/kg, Ketalar, Parke-Davis) and medetomidine hydrochloride (subcutaneous, 0.5 mg/kg, Domitor, Orion). The left femoral artery and vein were cannulated for measurements of blood pressure, arterial pH, blood gases, and blood glucose and drug and/or vehicle infusions. Cerebral blood flow was measured on-line with laser-Doppler flowmetry (Oxy-Flow, Oxford Optronix) as described...

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“…The latter are normally resident in the CNS [62], in close association with cerebral blood vessels during development and adulthood [63,64]. In contrast with what had been long assumed [65], Jin et al [66] showed that mast cell activation is the 'first responder' in this injurynot microglia. Although TNF-a is produced by many cells in response to stimuli, mast cells arrive 'armed' to initiate acute inflammation with their store of preformed TNF-a [67].…”

Section: Microglia Mast Cells and Nervous System Pathology (A) Neuromentioning

confidence: 99%

Mast cell–glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide

Skaper

Facci

2012

Phil. Trans. R. Soc. B

101

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Communication between the immune and nervous systems depends a great deal on pro-inflammatory cytokines. Both astroglia and microglia, in particular, constitute an important source of inflammatory mediators and may have fundamental roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Glial cells respond also to pro-inflammatory signals released from cells of immune origin. In this context, mast cells are of particular relevance. These immune-related cells, while resident in the CNS, are able to cross a compromised bloodspinal cord and blood-brain barrier in cases of CNS pathology. Emerging evidence suggests the possibility of mast cell-glia communication, and opens exciting new perspectives for designing therapies to target neuroinflammation by differentially modulating the activation of non-neuronal cells normally controlling neuronal sensitization-both peripherally and centrally. This review aims to provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of glia, neuro-immune interactions involving mast cells and the possibility that glia-mast cell interactions contribute to exacerbation of acute symptoms of chronic neurodegenerative disease and accelerated disease progression, as well as promotion of pain transmission pathways. Using this background as a starting point for discussion, we will consider the therapeutic potential of naturally occurring fatty acid ethanolamides, such as palmitoylethanolamide in treating systemic inflammation or blockade of signalling pathways from the periphery to the brain in such settings.

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Mast Cells Are Early Responders After Hypoxia-Ischemia in Immature Rat Brain

Cited by 127 publications

References 38 publications

Induction of Microglial Activation by Mediators Released from Mast Cells

Induction of Microglial Activation by Mediators Released from Mast Cells

Cerebral Mast Cells Mediate Blood-Brain Barrier Disruption in Acute Experimental Ischemic Stroke Through Perivascular Gelatinase Activation

Mast cell–glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide

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