β1-Integrin– and KV1.3 channel–dependent signaling stimulates glutamate release from Th17 cells

Birkner, Katharina; Wasser, Beatrice; Ruck, Tobias; Thalman, Carine; Luchtman, Dirk; Pape, Katrin; Schmaul, Samantha; Bitar, Lynn; Krämer-Albers, Eva-Maria; Stroh, Albrecht; Meuth, Sven G.; Zipp, Frauke; Bittner, Stefan

doi:10.1172/jci126381

Cited by 33 publications

(32 citation statements)

References 59 publications

(62 reference statements)

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“…Suppression of oxidative stress and reduction of chemokines that facilitate cell recruitment by acivicin might reduce myeloid cell numbers and decrease lesion size. Acivicin also regulates glutamate metabolism and leukotriene responses with potential effects on immune cell recruitment, neuronal and T cell functions 35 , 54 , 55 . Cell sorting and scRNA-seq studies will be required to determine the drug selectivity of acivicin at the single-cell level and its effects on oxidative stress resistance and additional prooxidant and inflammatory markers.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

et al. 2020

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Oxidative stress is a central part of innate-immune induced neurodegeneration. However, the transcriptomic landscape of the central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease, and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells (Tox-seq) identified a core oxidative stress gene signature coupled to coagulation and glutathione pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen (HTS) and oxidative stress gene network analysis, identified the glutathione regulating compound acivicin with potent therapeutic effects decreasing oxidative stress and axonal damage in chronic and relapsing multiple sclerosis (MS) models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable the discovery of selective neuroprotective strategies.

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Section: Discussionmentioning

confidence: 99%

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

et al. 2020

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“…Herein, using an unbiased analytic approach in an age‐ and sex‐matched cohort, we found that CD4 T‐cell populations differed in the peripheral blood of focal onset epilepsy subjects compared to HC, with a higher frequency of CD4 T cells in DRE. A detailed profile revealed a shift in the peripheral immune cell compartment of subjects with DRE toward the proinflammatory Th17/Th1 CD4 T‐cell subsets, which have been associated with neuroglial injury 15–17 . Providing biological support to a putative degenerative component of DRE, we found that levels of serum neurofilament light chain (sNfL), a marker of neuronal injury, are higher in DRE.…”

Section: Introductionmentioning

confidence: 79%

“…Proinflammatory Th17/Th1 CD4 T cells can exert cytotoxicity toward neurons, 15,17,33 whereas IL‐4 is considered neuroprotective 30 . Recent studies report a clinical deterioration in cognition over time in DRE subjects, especially in older individuals 4,34,35 .…”

Section: Resultsmentioning

confidence: 99%

“…Proinflammatory CD4 Th17 cells can cause direct neuroaxonal injury in vivo 16,17,33 and directly contribute to intractable seizure activity in an animal model of epilepsy, in part through secretion of IL‐17A and GM‐CSF 13 . Th17 cells can also release glutamate, 15 which could participate to excessive neuronal activation and excitotoxicity. We therefore hypothesize that the expansion of CD4 T cells and their shift toward a proinflammatory phenotype could be associated with CNS infiltration and neuroaxonal injury in DRE.…”

Section: Discussionmentioning

confidence: 99%

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Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug‐resistant epilepsy

et al. 2020

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ObjectiveAdult drug‐resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well‐controlled epilepsy (WCE).MethodsPeripheral blood mononuclear cells and serum from >120 age‐ and sex‐matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array.ResultsUsing a data‐driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)‐17A, IL‐22, tumor necrosis factor, interferon‐γ, and granulocyte‐macrophage colony–stimulating factor, but not anti‐inflammatory cytokines IL‐10 and IL‐4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17‐related circulating proinflammatory cytokines are elevated, but Th2‐related cytokine IL‐4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals.SignificanceOur data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.

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“…Astrocyte cultures were performed as previously described [ 47 ]. In brief, p0-p1 C57BL/6 brains were isolated and the hippocampus was stripped from the cortex.…”

Section: Methodsmentioning

confidence: 99%

Functional characteristics of Th1, Th17, and ex-Th17 cells in EAE revealed by intravital two-photon microscopy

Loos

Schmaul

Noll

et al. 2020

J Neuroinflammation

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Background T helper (Th) 17 cells are a highly plastic subset of T cells, which in the context of neuroinflammation, are able to acquire pathogenic features originally attributed to Th1 cells (resulting in so called ex-Th17 cells). Thus, a strict separation between the two T cell subsets in the context of experimental autoimmune encephalomyelitis (EAE) is difficult. High variability in culture and EAE induction protocols contributed to previous conflicting results concerning the differential contribution of Th1 and Th17 cells in EAE. Here, we systematically evaluate the role of different T cell differentiation and transfer protocols for EAE disease development and investigate the functional dynamics of encephalitogenic T cells directly within the inflamed central nervous system (CNS) tissue. Methods We compiled the currently used EAE induction protocols reported in literature and investigated the influence of the different Th1 and Th17 differentiation protocols as well as EAE induction protocols on the EAE disease course. Moreover, we assessed the cytokine profile and functional dynamics of both encephalitogenic Th1 and Th17 cells in the inflamed CNS using flow cytometry and intravital two-photon laser scanning microscopy. Lastly, we used astrocyte culture and adoptive transfer EAE to evaluate the impact of Th1 and Th17 cells on astrocyte adhesion molecule expression in vitro and in vivo. Results We show that EAE courses are highly dependent on in vitro differentiation and transfer protocols. Moreover, using genetically encoded reporter mice (B6.IL17A-EGFP.acRFP x 2d2/2d2.RFP), we show that the motility of interferon (IFN)γ-producing ex-Th17 cells more closely resembles Th1 cells than Th17 cells in transfer EAE. Mechanistically, IFNγ-producing Th1 cells selectively induce the expression of cellular adhesion molecules I-CAM1 while Th1 as well as ex-Th17 induce V-CAM1 on astrocytes. Conclusions The behavior of ex-Th17 cells in EAE lesions in vivo resembles Th1 rather than Th17 cells, underlining that their change in cytokine production is associated with functional phenotype alterations of these cells.

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β1-Integrin– and KV1.3 channel–dependent signaling stimulates glutamate release from Th17 cells

Cited by 33 publications

References 59 publications

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug‐resistant epilepsy

Functional characteristics of Th1, Th17, and ex-Th17 cells in EAE revealed by intravital two-photon microscopy

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