Dual Functions of Microglia in Ischemic Stroke

Qin, Chuan; Luo, Zhongxin; Tong, Xiao; Hu, Zi Wei; Yang, Sihua; Chen, Man; Bosco, Dale B.; Wu, Long Jun; Tian, Dai-Shi

doi:10.1007/s12264-019-00388-3

Cited by 385 publications

(275 citation statements)

References 149 publications

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“…We also showed that diabetes, as a chronic inflammatory disease, increases the number of activated ameboid microglia and worsens cognitive outcomes of stroke [12,13]. These studies suggest that the inflammatory status of microglia can be modulated by the microenvironment [14]. Given that 70% of stroke victims have pre-existing comorbidities such as diabetes and hypertension at the time of stroke, and diabetes worsens functional recovery and the severity of PSCI to an even greater extent, better understanding of the "primed" inflammatory microglia in the brain may allow us to modulate these cells to a beneficial phenotype to prevent progression of PSCI [8,15].…”

Section: Introductionsupporting

confidence: 54%

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

Jackson

Dumanli

Johnson

et al. 2020

J Neuroinflammation

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Introduction: Unfortunately, over 40% of stroke victims have pre-existing diabetes which not only increases their risk of stroke up to 2-6 fold, but also worsens both functional recovery and the severity of cognitive impairment. Our lab has recently linked the chronic inflammation in diabetes to poor functional outcomes and exacerbated cognitive impairment, also known as post-stroke cognitive impairment (PSCI). Although we have shown that the development of PSCI in diabetes is associated with the upregulation and the activation of pro-inflammatory microglia, we have not established direct causation between the two. To this end, we evaluated the role of microglia in the development of PSCI.Methods: At 13 weeks of age, diabetic animals received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles targeting the colony stimulating factor 1 receptor (CSF1R). After 14 days, animals were subjected to 60 min middle cerebral artery occlusion (MCAO) or sham surgery. Adhesive removal task (ART), novel object recognition (NOR), and 2-trial Y-maze were utilized to evaluate sensorimotor and cognitive function. Tissue from freshly harvested brains was analyzed by flow cytometry and immunohistochemistry.Results: CSF1R silencing resulted in a 94% knockdown of residential microglia to relieve inflammation and improve myelination of white matter in the brain. This prevented cognitive decline in diabetic animals. Conclusion: Microglial activation after stroke in diabetes may be causally related to the development of delayed neurodegeneration and PSCI.

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Section: Introductionsupporting

confidence: 54%

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

Jackson

Dumanli

Johnson

et al. 2020

J Neuroinflammation

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“…Microglia are the principal immune cells responding to the pathological changes at the primary injury site after ischemic stroke (73,74). Accumulated data indicate that microglial activation is a key feature of the secondary thalamic injury in both rodents and humans (75,76).…”

Section: Microgliamentioning

confidence: 99%

Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke

et al. 2020

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Stroke is one of the major causes of chronic disability worldwide and increasing efforts have focused on studying brain repair and recovery after stroke. Following stroke, the primary injury site can disrupt functional connections in nearby and remotely connected brain regions, resulting in the development of secondary injuries that may impede long-term functional recovery. In particular, secondary degenerative injury occurs in the connected ipsilesional thalamus following a cortical stroke. Although secondary thalamic injury was first described decades ago, the underlying mechanisms still remain unclear. We performed a systematic literature review using the NCBI PubMed database for studies that focused on the secondary thalamic degeneration after cortical ischemic stroke. In this review, we discussed emerging studies that characterized the pathological changes in the secondary degenerative thalamus after stroke; these included excitotoxicity, apoptosis, amyloid beta protein accumulation, blood-brain-barrier breakdown, and inflammatory responses. In particular, we highlighted key findings of the dynamic inflammatory responses in the secondary thalamic injury and discussed the involvement of several cell types in this process. We also discussed studies that investigated the effects of blocking secondary thalamic injury on inflammatory responses and stroke outcome. Targeting secondary injuries after stroke may alleviate network-wide deficits, and ultimately promote stroke recovery.

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“…Traumatic spinal cord injury (SCI) always results in an excessive inflammatory response, which contributes to secondary tissue damage that is characterized by the formation of an ellipsoidal, loculated cystic cavity [1][2][3][4]. Inflammation is initiated by infiltrating leukocytes or resident microglia that bind with endogenous damageassociated molecular pattern (DAMP) molecules through their pattern recognition receptors on the cell surface [5].…”

Section: Introductionmentioning

confidence: 99%

SOCS3 Attenuates GM-CSF/IFN-γ-Mediated Inflammation During Spontaneous Spinal Cord Regeneration

Zhang

et al. 2020

Neurosci. Bull.

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SOCS3, a feedback inhibitor of the JAK/STAT signal pathway, negatively regulates axonal regrowth and inflammation in the central nervous system (CNS). Here, we demonstrated a distinct role of SOCS3 in the injured spinal cord of the gecko following tail amputation. Severing the gecko spinal cord did not evoke an inflammatory cascade except for an injury-stimulated elevation of the granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN-c) cytokines. Simultaneously, the expression of SOCS3 was upregulated in microglia, and unexpectedly not in neurons. Enforced expression of SOCS3 was sufficient to suppress the GM-CSF/IFN-c-driven inflammatory responses through its KIR domain by attenuating the activities of JAK1 and JAK2. SOCS3 was also linked to GM-CSF/IFN-c-induced crosstolerance. Transfection of adenovirus overexpressing SOCS3 in the injured cord resulted in a significant decrease of inflammatory cytokines. These results reveal a distinct role of SOCS3 in the regenerating spinal cord, and provide new hints for CNS repair in mammals.

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Dual Functions of Microglia in Ischemic Stroke

Cited by 385 publications

References 149 publications

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke

SOCS3 Attenuates GM-CSF/IFN-γ-Mediated Inflammation During Spontaneous Spinal Cord Regeneration

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