Inflammation in Ischemic Brain Injury: Timing Is Important
Abstract
Inflammation is a defense reaction against diverse insults that serves to remove noxious agents and to limit their detrimental effects. There is increasing evidence that post-ischemic inflammation plays an important role in brain ischemia. However, whether inflammatory processes are deleterious or beneficial to recovery is presently a matter of debate and controversy. Experimentally and clinically, stroke is followed by an acute and a prolonged inflammatory response characterized by the production of inflammatory cytokines, leukocyte and monocyte infiltration in the brain, and the activation of resident glial cells. These events may contribute to ischemic brain injury. Several groups report conflicting results regarding the role of inflammation and effects of anti-inflammatory treatments in cerebral ischemia. Experimental studies employing knockout mice for different cytokines and chemokines provide only partial answers. This highlights the importance of clarifying the role of the immune response in pathological changes at the site of ischemic lesions in the brain. Here, we describe dual effects of the brain's inflammatory response and new evidence for a neuroprotective role of proliferating microglial cells in ischemia. In addition, we discuss a potential role of post-ischemic inflammation in brain regeneration and modulation of synaptic plasticity.
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Resident macrophages and invading myelomonocytic cells release cytokines, chemokines, ROS, NETs, and MMP-9, which lead to further disruption of the BBB, brain edema, neuronal death, and hemorrhagic transformation.
“Resident macrophages and invading myelomonocytic cells release cytokines (such as TNFα and IL-1β), chemokines, reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and MMP-9, which lead to further disruption of the BBB, brain edema, neuronal death, and hemorrhagic transformation (Fig. 4) (136).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [136]
The acute phase after ischemia is characterized by rapid release of DAMPs, which are sensed by endothelial cells as well as resident and circulating immune cells.
“The acute phase after ischemia is characterized by the rapid-release DAMPs, which are sensed by endothelial cells as well as resident and circulating immune cells.”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [136]
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“All three cell types can contribute to the proinflammatory cytokine responses following ischemia (Gibson et al. 2005; Panickar and Norenberg 2005; Kriz 2006 ).”
BackgroundHyperbaric Oxygen Therapy in Acute Ischemic Stroke: A Review
Ding, Z., Tong, W. C., Lu, X., & Peng, H. (2013) · Interventional Neurology · doi:10.1159/000362677 · Cited by 57 · see citing works
PET imaging of the neurovascular interface in cerebrovascular disease
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“In most cases, AD patients have decreased learning and memory, cognitive impairment, and social and emotional disorders [3,108].”
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“Diverse pathological CNS conditions including infection, trauma or neurodegenerative disorders induce an inflammatory response that is mediated by activated microglia, astrocytes, and infiltrating macrophages (Kriz 2006; Jin et al. 2010).”
BackgroundSensitization and tolerization to brain antigens in stroke
Becker, K. J. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.07.027 · Cited by 50 · see citing works
Tracking Transplanted Bone Marrow Stem Cells and Their Effects in the Rat MCAO Stroke Model
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“How these stem cell-induced changes modify the welldocumented inflammatory response which occurs in the host brain after experimental stroke [18,35,38,39] is only now being explored.”
BackgroundTargeting Dopamine in Acute Traumatic Brain Injury.
Bales, J. W., Kline, A. E., Wagner, A. K., & Dixon, C. E. (2010) · PubMed · doi:10.2174/1877381801002010119 · Cited by 55 · see citing works
“However, difficulties remain due to concerns over the potential neuroprotective role of inflammatory cells and worries over what side effects direct inhibition of inflammation may cause [117, 118].”
Mellergård, P., Sjögren, F., & Hillman, J. (2010) · British Journal of Neurosurgery · doi:10.3109/02688690903521605 · Cited by 47 · see citing works
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Hypothermia and brain inflammation after cardiac arrest
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“Immune response and inflammatory processes start immediately after onset of ischemia and evolve through several phases.[42] Our understanding of inflammation after global brain ischemia is partly derived from the expanding knowledge on inflammation after focal brain ischemia although differences exist.”
BackgroundThe potential roles of dopamine in traumatic brain injury: a preclinical and clinical update.
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“During the early phase, the proliferating microglia secrete insulin-like growth factor one (IGF-1), which is neuroprotective (Kriz, 2006).”
Shah, M.-A., Kang, J.-B., Park, D.-J., Kim, M. O., & Koh, P. (2022) · Neuroscience Letters · doi:10.1016/j.neulet.2022.136495 · Cited by 43 · see citing works
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“Conversely, some aspects of the innate immune response can facilitate later tissue repair and functional recovery.(34,39) Therefore, the timing of anti-inflammatory treatment may crucially affect the outcome.”
BackgroundShi, W., Zhao, C.-Z., Zhao, B., Shi, Q., Zhang, L., Wang, Y., Fang, S., Lu, Y., Zhang, W., & Wei, E. (2012) · Neuroscience Bulletin · doi:10.1007/s12264-012-1281-z · Cited by 43 · see citing works
“Post-ischemic inflammation involves the accumulation of inflammatory cells (resident microglia and blood-derived leukocytes) and the induction of pro-inflammatory molecules([20-22]).”
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“By these molecules, infiltrating neutrophils amplify a cerebral inflammatory response that may exacerbate post-ischemic brain damage (49,51,52).”
Zhang, Y.-J., Song, J.-R., & Zhao, M. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.08.008 · Cited by 39 · see citing works
Influence of Inflammation on Poststroke Plasticity
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“It has been shown that these ischemic events contribute to brain injury, but, on the other hand, inflammatory cells can participate in tissue remodeling following brain damage [47].”
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“Cytokines, as major effectors of the inflammatory cascade, play a key role in the nerve cell response to brain injury and may be beneficial or, when secreted in an imbalanced fashion, detrimental to neurons (Kriz, 2006).”
BackgroundOliveira, M. C., Voltarelli, J. C., Sanberg, P. R., Allickson, J. G., Kuzmin‐Nichols, N., Garbuzova-Davis, S. N., & Borlongan, C. V. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.05.010 · Cited by 35 · see citing works
“(2004) demonstrated that the inhibition of strocyte activation following spinal cord injury increased neuron eath, possibly because even in an injured environment, astrocytes till maintain some supportive functions, including the secretion f neurotrophic factors (NGF and BDGF), which are important for issue repair and…”
BackgroundCatecholaminergic based therapies for functional recovery after TBI
Osier, N. D., & Dixon, C. E. (2015) · Brain Research · doi:10.1016/j.brainres.2015.12.026 · Cited by 35 · see citing works
“However, there remains some concern that there is a role for inflammatory cells in post-TBI neuroprotection which may complicate treatment with antiinflammatory agents (Ekdahl et al., 2009; Kriz, 2006).”
BackgroundProtein methionine oxidation augments reperfusion injury in acute ischemic stroke
Gu, S. X., Blokhin, I. O., Wilson, K. M., Dhanesha, N., Doddapattar, P., Grumbach, I. M., Chauhan, A. K., & Lentz, S. R. (2016) · JCI Insight · doi:10.1172/jci.insight.86460 · Cited by 35 · see citing works
“The impact of NF-κB transcriptional activity on stroke outcomes appears to be temporally regulated by the timing of NF-κB activation during stroke progression (10, 39).”
Li, S., Lu, X., Shao, Q., Chen, Z., Huang, Q., Jiao, Z., Huang, X., Yue, M., Peng, J., Zhou, X., et al. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00893 · Cited by 33 · see citing works
- Authors
- Kriz, J.
- Venue
- Critical Reviews™ in Neurobiology
- Publisher
- Begell House
- Published
- 2006
- Volume
- 18
- Issue
- 1-2
- Pages
- 145-157
- ISSN
- 0892-0915 (ISSN-L)
- OpenAlex
- W1982308497
- Cited by
- 238
- References
- 0
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 13 · 2023: 12 · 2022: 11 · 2021: 8 · 2020: 7 · 2019: 21 · 2018: 10 · 2017: 8 · 2016: 13 · 2015: 13 · 2014: 21 · 2013: 23 · 2012: 18
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Critical Reviews in Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- post-ischemic inflammation, cerebral ischemia, stroke, neuroinflammation, inflammatory cytokines, leukocyte infiltration, monocyte infiltration, glial activation, microglia, neuroprotection, anti-inflammatory therapy, cytokine knockout mice, brain regeneration, synaptic plasticity
- MeSH terms
- Animals, Brain Ischemia, Chemotaxis, Leukocyte, Encephalitis, Gliosis, Humans, Cytokines, Microglia, Cytoprotection, Brain Infarction, Cell Proliferation
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