Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke

Szalay, Gergely; Martinecz, Bernadett; Lénárt, Nikolett; Környei, Zsuzsanna; Orsolits, Barbara; Judák, Linda; Császár, Eszter; Fekete, Rebeka; West, Brian L.; Katona, Gergely; Rózsa, Balázs; Dénes, Ádám

doi:10.1038/ncomms11499

Cited by 482 publications

(468 citation statements)

References 64 publications

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“…Selective ablation of proliferating microglia after focal ischemia in a transgenic mouse also demonstrated exacerbation of stroke injury with an altered inflammatory response [64]. A similar beneficial effect of microglia in stroke was reported in a study where there was a 60 % increase in infarct size by selective elimination of microglia, which the effect was reversed by repopulating the cells [65]. In contrast, microglia ablation was either protective or had no effect in models of other neurodegenerative diseases, including Alzheimer's disease [66], amyotrophic lateral sclerosis [67], and experimental autoimmune encephalomyelitis [68].…”

Section: Microgliamentioning

confidence: 54%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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Section: Microgliamentioning

confidence: 54%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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“…Microglia are an important inflammatory cell in the neocortex (Dheen et al, 2007) and have been shown to rapidly respond to brain injury (Davalos et al, 2005; Szalay et al, 2016). Therefore, we sought to determine whether there was a change in microglial density following both forms of TBI as well as whether there was a relationship between microglial density and serotonin axon loss.…”

Section: Resultsmentioning

confidence: 99%

Serotonin axons in the neocortex of the adult female mouse regrow after traumatic brain injury

Kajstura

Dougherty

Linden

2017

J of Neuroscience Research

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It is widely held that injured neurons in the central nervous system do not undergo axonal regrowth. However, there is mounting evidence that serotonin axons are a notable exception. Serotonin axons undergo long-distance regrowth in the neocortex after amphetamine lesion and, following a penetrating stab injury, they can regrow from cut ends to traverse the stab rift. Traumatic brain injury (TBI) is clinically prevalent and can lead to pathologies such as depression that are related to serotonergic dysfunction. Thus, whether serotonin axons can regrow after TBI is an important question. We used two models for TBI, a persistent open skull condition and controlled cortical impact, to evoke injury in adult female mouse neocortex and assessed serotonin axon density one week, one month, and three months after injury by serotonin transporter immunohistochemistry. We found that following both forms of TBI, serotonin axon density is decreased posterior but not anterior to the injury site when measured in layer 1 at one week post-surgery, and that serotonin axons are capable of regrowing into the distal zone to increase density by one month post-surgery. This pattern is consistent with the anterior-to-posterior course of serotonin axons in the neocortex. TBI in these models is associated with significant reactive astrogliosis both anterior and posterior to the impact, but the degree of reactive astrogliosis is not correlated with serotonin axon density when measured one week after TBI. Microglial density remains constant following both types of injuries, but microglial condensation was detected one week after controlled cortical impact.

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“…Brain ischemia activates microglia that can damage neural structure or facilitate neural repair, depending on timing and context (52)(53)(54)(55). Microglia express IL-15 receptors and thus could be receptive to astrocytic IL-15.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Yao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

148

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Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) Infiltrating leukocytes such as lymphocytes are major effectors of postischemic brain inflammation (1-6). The phenotype and function of infiltrating lymphocytes are largely dictated by organspecific intrinsic factors during inflammatory responses (7-9), and such factors in the brain are unique in terms of cellular constituents, blood-brain barrier (10-12), and microenvironment (1-3, 7). As the most abundant cell type in the CNS, astrocytes constitute nearly 50% of the human brain's volume. Astrocytes contribute to the regulation of neural transmission, survival of neurons and other glia cells, and integrity of the blood-brain barrier. In the inflamed CNS, astrocytes engage in significant cross-talk with CNS-infiltrating immune cells by providing a major source of the proinflammatory cytokines and chemokines, thereby activating infiltrating lymphocytes. Evidence has shown that astrocytes can exert potent proinflammatory functions by producing factors including monocyte chemotactic protein-1 (MCP-1/CCL2), interleukin 1 beta (IL-1β), interleukin-6 (IL-6), etc., as their primary mode of action after CNS injury. In addition, astrocytes are considered as important nonprofessional antigen-presenting cells. Depending on the stage of brain pathology, astrocytes also possess antiinflammatory properties such as scar formation and restriction of inflammation by producing transforming growth factor-β (13,14). Recent studies have shown that the inhibition of astrocytes correlates with decreased infarct size (15,16) and that treatments capable of decreasing infarct size are often accompanied by attenuated astrocyte responses. These findings suggest a detrimental role for astrocytes after brain ischemia (15-18). However, still unknown are whether and how astrocytes shape acute CNS immune responses in the context of a postischemic brain and whether this process has any clinical significance.IL-15 belongs to a family of cytokines using the common γ-chain as a component of their receptors (19,20). IL-15 interacts specifically with the high-affinity IL-15 receptor α (IL-15Rα) and binds to IL-2/IL-15Rβ and a common γ-chain expressed by target cells (21-23). In the periphery, monocytes and dendritic cells are the main sources of 25). IL-15 maintains homeostasis and cytotoxic activities of lymphocytes that bear its receptor [i.e., natural killer (NK) and CD8 + T cells] (19,20). Some studies have demonstrated that IL-15 contributes to the immunopathology of several inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease (26,27). Despite recent studies suggesting astrocytes as a major...

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Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke

Cited by 482 publications

References 64 publications

Microglia and Monocyte-Derived Macrophages in Stroke

Microglia and Monocyte-Derived Macrophages in Stroke

Serotonin axons in the neocortex of the adult female mouse regrow after traumatic brain injury

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

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