Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke

Liesz, Arthur; Zhou, Wei; Mracskó, Éva; Karcher, Simone; Bauer, Henrike; Schwarting, Sönke; Sun, Li; Bruder, Dunja; Stegemann, Sabine; Cerwenka, Adelheid; Sommer, Clemens; Dalpke, Alexander H.; Veltkamp, Roland

doi:10.1093/brain/awr008

Cited by 356 publications

(379 citation statements)

References 71 publications

(103 reference statements)

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“…However, some potential targets in the immune system have not been fully characterized (37). Many defined targets have been described that show promise (7,(36)(37)(38)(39)(40)(41)(42). Cryab is notable because it is endogenously produced after stroke, and has known antiinflammatory effects on inflammatory immune responses (11).…”

Section: Discussionmentioning

confidence: 99%

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Arac

Brownell

Rothbard

et al. 2011

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

130

128

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Tissue plasminogen activator is the only treatment option for stroke victims; however, it has to be administered within 4.5 h after symptom onset, making its use very limited. This report describes a unique target for effective treatment of stroke, even 12 h after onset, by the administration of αB-crystallin (Cryab), an endogenous immunomodulatory neuroprotectant. In Cryab −/− mice, there was increased lesion size and diminished neurologic function after stroke compared with wild-type mice. Increased plasma Cryab was detected after experimental stroke in mice and after stroke in human patients. Administration of Cryab even 12 h after experimental stroke reduced both stroke volume and inflammatory cytokines associated with stroke pathology. Cryab is an endogenous anti-inflammatory and neuroprotectant molecule produced after stroke, whose beneficial properties can be augmented when administered therapeutically after stroke.

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Section: Discussionmentioning

confidence: 99%

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Arac

Brownell

Rothbard

et al. 2011

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

130

128

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“…Flow cytometric analysis showed a dominance of the CD4 1 subset (19, 35). B-lymphocytes have rarely been analyzed, and their total numbers were similar to those of Tcells (35,53). Several possible roles of B-cells have been postulated in stroke patients, having disease enhancing as well as protective effects (49).…”

Section: Relation Of the Inflammatory Reaction To Blood Vesselsmentioning

confidence: 99%

Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts

et al. 2017

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Inflammatory mechanisms, involving granulocytes, T-cells, B-cells, macrophages and activated microglia, have been suggested to play a pathogenic role in experimental models of stroke and may be targets for therapeutic intervention. However, knowledge on the inflammatory response in human stroke lesions is limited. Here, we performed a quantitative study on the inflammatory reaction in human ischemic infarct lesions. We found increased numbers of T-lymphocytes, mainly CD8 1 cells, but not of B-lymphocytes. Their number was very low in comparison to that seen in inflammatory diseases of the central nervous system and they did not show signs of activation. Polymorphonuclear leukocytes were present in meninges and less prominently in the perivascular space in early lesions, but their infiltration into the lesioned tissue was sparse with the exception of a single case. Microglia were lost in the necrotic core of fresh lesions, their number was increased in the surrounding penumbra, apparently due to proliferation. Using TMEM119 as a marker for the resident microglia pool, macrophages in lesions were in part derived from the original microglia pool, depending on the lesion stage. Most microglia and macrophages revealed a proinflammatory activation pattern, expressing molecules involved in phagocytosis, oxidative injury, antigen presentation and iron metabolism and had partially lost the expression of P2RY12, an antigen expressed on homeostatic ("resting") microglia in rodents. At later lesion stages, the majority of macrophages showed intermediate activation patterns, expressing pro-inflammatory and anti-inflammatory markers. Microglia in the normal white matter of controls and stroke patients were already partly activated toward a pro-inflammatory phenotype. Our data suggest that the direct contribution of lymphocytes and granulocytes to active tissue injury in human ischemic infarct lesions is limited and that stroke therapy that targets pro-inflammatory microglia and macrophage activation may be effective.

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“…Transgenic animals deficient in lymphocytes consistently have smaller infarcts in different stroke models [23][24][25][26]. Moreover, antibody-mediated depletion of CD4 + , CD8 + , and γδ T cells reduced infarct volume and improved functional outcome [25,[27][28][29]. The dynamics of this deleterious role of different proinflammatory T cells have not been fully elucidated.…”

Section: Immune Mechanismsmentioning

confidence: 99%

Clinical Trials of Immunomodulation in Ischemic Stroke

2016

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Inflammatory mechanisms are currently considered as a prime target for stroke therapy. There is evidence from animal studies that immune signals and mediators can have both detrimental and beneficial effects in particular stages of the disease process. Moreover, several of these mechanisms are turned on with sufficient delay after ischemia onset to make them amenable to therapeutic intervention. Several clinical proof-of concept trials have investigated the efficacy of different immunomodulatory approaches in patients with stroke. Trials targeting the innate immune system have focused on reduction of microglial activation, inhibition of neutrophil migration, and interleukin-1 receptor blockade, suggesting that interleukin-1 receptor blockade may be a promising strategy. Studies aiming at halting T-cell migration have also been undertaken with controversial findings regarding prevention of infarct growth in neuroimaging studies. Consistently, recent proof-of-concept trials targeting lymphocytes with drugs such as natalizumab and fingolimod have yielded some promising results on clinical endpoints, but confirmation in larger trials is needed. At present, the understanding of the role of immune mechanisms in neurorepair and neurodegeneration is limited. Improving long-term brain function by mitigating prolonged neuroinflammation that was triggered by acute brain injury could be a strategy in addition to neuroprotection.

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Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke

Cited by 356 publications

References 71 publications

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts

Clinical Trials of Immunomodulation in Ischemic Stroke

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