Double-negative T cells remarkably promote neuroinflammation after ischemic stroke

Meng, Hailan; Zhao, Haoran; Cao, Xiang; Hao, Junwei; Zhang, He; Liu, Yi; Zhu, Min–Sheng; Fan, Lizhen; Weng, Leihua; Lai, Qi; Wang, Xiaoying; Xu, Yun

doi:10.1073/pnas.1814394116

Cited by 140 publications

(126 citation statements)

References 43 publications

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“…Consequently, CD4 − CD8 − T cells have been described in promoting neuroin ammation after ischemic stroke, [41] as well as preventing autoimmune diseases and graft-versus-host disease (GvHD). [42][43][44][45] Interestingly, a recent study revealed the potential role of CD4 − CD8 − T cells in limiting alloreactive immune response by suppressing the CD4 T cell functionality.…”

Section: Resultsmentioning

confidence: 99%

Differential Leukocyte miRNA Responses Following Pan T Cell, Allorecognition and Allosecretome-Based Therapeutics Activation

Yang

Toyofuku

Scott

2020

Preprint

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Background Effective immunomodulation of T cell responses is critical in treating both autoimmune diseases and cancer. Our previous studies have demonstrated that secretomes derived from control or methoxypolyethylene glycol (mPEG) mixed lymphocyte alloactivation assays exerted potent immunomodulatory activity that was mediated by microRNAs (miRNA). In this study, the immunomodulatory effects of biomanufactured miRNA-based allo-secretome therapeutics (SYN, TA1, IA1 and IA2) were compared to Pan T cell activators (PHA and anti-CD3/CD28) and alloactivation (MHC-disparate donors; ± mPEG grafting). The differential effects of these activation strategies on resting PBMC were assessed via T cell differentiation and proliferation as well as the differential expression of multiple miRNA.Results Mitogen-induced PBMC proliferation (average of > 85%) significantly exceed that arising from either allostimulation (~ 30%) or the proinflammatory IA1 secretome product (~ 12%). Consequent to stimulation, the ratio of CD4 to CD8 cells of the resting PBMC (CD4:CD8; 1.7 ± 0.1) decreased in the Pan-T cell, allrecognition and IA1 activated cells (average of 1.1 ± 0.2; 1.2 ± 0.1 and 1.0 ± 0.1). These changes arose consequent to the expansion of both CD4+CD8+ and CD4-CD8- populations and the shrinkage of the CD4 subset relative to the expansion of the CD8 T cells. Most importantly, this study demonstrated that these activation strategies exert profoundly unique effects on the differential expression of miRNA within the treated PBMC and that these 'differential patterns of miRNA expression' are associated with significant differences in cellular differentiation and biological function.Conclusions These findings support the concept that the 'differential pattern of miRNA expression', not a change in a single miRNA, governs the biologic immune response in a 'lock and key' manner. The biomanufacturing of miRNA-enriched secretome biotherapeutics may be a successful approach for producing miRNA cocktails (e.g., TA1 and IA1) that replicate the normal biological 'lock and key' miRNA configuration necessary for the systemic treatment of autoimmune diseases (TA1) or enhancing the endogenous immune response to cancer (IA1).

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Section: Resultsmentioning

confidence: 99%

Differential Leukocyte miRNA Responses Following Pan T Cell, Allorecognition and Allosecretome-Based Therapeutics Activation

Yang

Toyofuku

Scott

2020

Preprint

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“…It is intriguing that infiltrating DNTs are located close to the microglial population in the ischemic brain territories of both MCAO mice and stroke patients. Furthermore, DNT‐intrinsic PTPN2 and FasL may collaboratively regulate the level of M1 microglia via the production of TNF‐α, which amplifies neuroinflammation and exacerbates brain injury after stroke . Therefore, infiltrating lymphocytes are critical driving forces for modulating microglia‐mediated neuroinflammation and ischemic brain injury .…”

Section: Microglia‐neighboring Cells Crosstalk and Interventions For mentioning

confidence: 99%

“…Furthermore, DNT-intrinsic PTPN2 and FasL may collaboratively regulate the level of M1 microglia via the production of TNF-α, which amplifies neuroinflammation and exacerbates brain injury after stroke. 111 Therefore, infiltrating lymphocytes are critical driving forces for modulating microglia-mediated neuroinflammation and ischemic brain injury. 112 These findings highlight the potential for targeting microglia-lymphocyte interactions for the development of therapies to reduce CNS insult, including stroke.…”

Section: T Cells or By Releasing Inflammatory Cytokines Via Tregs Andmentioning

confidence: 99%

Potential microglia‐based interventions for stroke

Huang

Yang

et al. 2020

CNS Neurosci Ther

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A large number of families worldwide suffer from the physical and mental burden posed by stroke. An increasing number of studies aimed at the prevention and treatment of stroke have been conducted. Specifically, manipulating the immune response to stroke is under intense investigation. Microglia are the principal immune cells in the brain and are the first line of defense against the pathophysiology induced by stroke. Increasing evidence has suggested that microglia play diverse roles that depend on dynamic interactions with neurons, astrocytes, and other neighboring cells both in the normal brain and under pathological conditions, including stroke. Moreover, there are dynamic alterations in microglial functions with respect to aging and sex differences in the human brain, which offer a deep understanding of the conditions of stroke patients of different ages and sex. Hence, we review the dynamic microglial reactions caused by aging, sex, and crosstalk with neighboring cells both in normal conditions and after stroke and relevant potential interventions.

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“…The modified neurological severity score (mNSS) and grip strength were employed to assess the neurological performance of the MCAO mice 24 h after PJ34 administration as described previously (Meng et al, 2019). mNSS score: the test was performed mainly to assess the motor, reflex, sensory, and balance deficits with a score range from 0 to 18 (0: normal; 18: maximal deficit score).…”

Section: Behavior Testmentioning

confidence: 99%

Delayed PARP-1 Inhibition Alleviates Post-stroke Inflammation in Male Versus Female Mice: Differences and Similarities

Chen

et al. 2020

Front. Cell. Neurosci.

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Post-stroke inflammation is almost involved in the whole process of stroke pathogenesis, which serves as a prime target for developing new stroke therapies. Despite known sex differences in the incidence and outcome of stroke, few preclinical or clinical studies take into account sex bias in treatment. Recent evidence suggests that poly (ADP-ribose) polymerase (PARP)-1 inhibitor exerts sex-specific neuroprotection in the ischemic stroke. This study was aimed to investigate the effects of delayed PARP-1 inhibition on post-stroke inflammation and possible sexual dimorphism, and explore the possible relevant mediators. In male and female C57BL/6 mice subjected to transit middle cerebral artery occlusion (MCAO), we found that delayed treatment of PARP-1 inhibitor at 48 h following reperfusion could comparably alleviate neuro-inflammation at 72 h after stroke. Whereas, more remarkable reduction of iNOS and MMP9 induced by PARP-1 inhibition were found in male MCAO mice, and the improvement of behavioral outcomes was more prominent in male MCAO mice. In addition, we further identified that PARP-1 inhibitor might equivalently suppress microglial activation in males and females in vivo and in vitro. With proteomic analysis and western blotting assay, it was found that stroke-induced peroxiredoxin-1 (Prx1) expression was significantly affected by PARP-1 inhibition. Interestingly, injection of recombinant Prx1 into the ischemic core could block the anti-inflammatory effects of PARP-1 inhibitor in the experimental stroke. These findings suggest that PARP-1 inhibitor has effects on regulating microglial activation and post-stroke inflammation in males and females, and holds promise as a novel therapeutic agent for stroke with extended therapeutic time window. Efforts need to be made to delineate the actions of PARP-1 inhibition in stroke, and here we propose that Prx1 might be a critical mediator.

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Double-negative T cells remarkably promote neuroinflammation after ischemic stroke

Cited by 140 publications

References 43 publications

Differential Leukocyte miRNA Responses Following Pan T Cell, Allorecognition and Allosecretome-Based Therapeutics Activation

Differential Leukocyte miRNA Responses Following Pan T Cell, Allorecognition and Allosecretome-Based Therapeutics Activation

Potential microglia‐based interventions for stroke

Delayed PARP-1 Inhibition Alleviates Post-stroke Inflammation in Male Versus Female Mice: Differences and Similarities

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