Dectin-1/Syk signaling triggers neuroinflammation after ischemic stroke in mice

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Abstract

Background

Dendritic cell-associated C-type lectin-1 (Dectin-1) receptor has been reported to be involved in neuroinflammation in Alzheimer’s disease and traumatic brain injury. The present study was designed to investigate the role of Dectin-1 and its downstream target spleen tyrosine kinase (Syk) in early brain injury after ischemic stroke using a focal cortex ischemic stroke model.

Methods

Adult male C57BL/6 J mice were subjected to a cerebral focal ischemia model of ischemic stroke. The neurological score, adhesive removal test, and foot-fault test were evaluated on days 1, 3, 5, and 7 after ischemic stroke. Dectin-1, Syk, phosphorylated (p)-Syk, tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) expression was analyzed via western blotting in ischemic brain tissue after ischemic stroke and in BV2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro. The brain infarct volume and Iba1-positive cells were evaluated using Nissl’s and immunofluorescence staining, respectively. The Dectin-1 antagonist laminarin (LAM) and a selective inhibitor of Syk phosphorylation (piceatannol; PIC) were used for the intervention.

Results

Dectin-1, Syk, and p-Syk expression was significantly enhanced on days 3, 5, and 7 and peaked on day 3 after ischemic stroke. The Dectin-1 antagonist LAM or Syk inhibitor PIC decreased the number of Iba1-positive cells and TNF-α and iNOS expression, decreased the brain infarct volume, and improved neurological functions on day 3 after ischemic stroke. In addition, the in vitro data revealed that Dectin-1, Syk, and p-Syk expression was increased following the 3-h OGD and 0, 3, and 6 h of reperfusion in BV2 microglial cells. LAM and PIC also decreased TNF-α and iNOS expression 3 h after OGD/R induction.

Conclusion

Dectin-1/Syk signaling plays a crucial role in inflammatory activation after ischemic stroke, and further investigation of Dectin-1/Syk signaling in stroke is warranted.

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Most cited references 48

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Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.

Olaf Gross, Hendrik Poeck, Michael Bscheider … (2009)

Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1beta (IL-1beta) is a key pro-inflammatory factor in innate antifungal immunity. The mechanism by which the mammalian immune system regulates IL-1beta production after fungal recognition is unclear. Two signals are generally required for IL-1beta production: an NF-kappaB-dependent signal that induces the synthesis of pro-IL-1beta (p35), and a second signal that triggers proteolytic pro-IL-1beta processing to produce bioactive IL-1beta (p17) via Caspase-1-containing multiprotein complexes called inflammasomes. Here we demonstrate that the tyrosine kinase Syk, operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL-1beta synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signalling for pro-IL-1beta synthesis selectively uses the Card9 pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmalogical inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (also known as NALP3) was identified as the critical NOD-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (Pycard) for Caspase-1 (Casp1) activation and pro-IL-1beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, we show that Nlrp3-deficient mice are hypersusceptible to Candida albicans infection. Thus, our results demonstrate the molecular basis for IL-1beta production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.

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Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals.

Bruno Martin, Keiji Hirota, Daniel Cua … (2009)

Gammadelta T cells are an innate source of interleukin-17 (IL-17), preceding the development of the adaptive T helper 17 (Th17) cell response. Here we show that IL-17-producing T cell receptor gammadelta (TCRgammadelta) T cells share characteristic features with Th17 cells, such as expression of chemokine receptor 6 (CCR6), retinoid orphan receptor (RORgammat), aryl hydrocarbon receptor (AhR), and IL-23 receptor. AhR expression in gammadelta T cells was essential for the production of IL-22 but not for optimal IL-17 production. In contrast to Th17 cells, CCR6(+)IL-17-producing gammadelta T cells, but not other gammadelta T cells, express Toll-like receptors TLR1 and TLR2, as well as dectin-1, but not TLR4 and could directly interact with certain pathogens. This process was amplified by IL-23 and resulted in expansion, increased IL-17 production, and recruitment of neutrophils. Thus, innate receptor expression linked with IL-17 production characterizes TCRgammadelta T cells as an efficient first line of defense that can orchestrate an inflammatory response to pathogen-derived as well as environmental signals long before Th17 cells have sensed bacterial invasion.

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Identification of a dendritic cell receptor that couples sensing of necrosis to immunity

David Sancho, Olivier P Joffre, Anna M. Keller … (2009)

Injury or impaired clearance of apoptotic cells leads to the pathological accumulation of necrotic corpses, which induce an inflammatory response that initiates tissue repair1. In addition, antigens present within necrotic cells can sometimes provoke a specific immune response2-4 and it has been argued that necrosis could explain adaptive immunity in seemingly infection-free situations, such as after allograft transplantation or in spontaneous and therapy-induced tumour rejection5, 6. In the mouse, the CD8α+ subset of dendritic cells (DC) phagocytoses dead cell remnants and crossprimes CD8+ T cells against cell-associated antigens7. Here, we show that CD8α+ DC utilise CLEC9A (DNGR-1), a recently-characterised C-type lectin8-10, to recognise a preformed signal that is exposed on necrotic cells. Loss or blockade of CLEC9A does not impair uptake of necrotic cell material by CD8α+ DC but specifically reduces crosspresentation of dead cell-associated antigens in vitro and decreases the immunogenicity of necrotic cells in vivo. The function of CLEC9A requires a key tyrosine residue within its intracellular tail that allows recruitment and activation of the tyrosine kinase Syk, which is also essential for crosspresentation of dead cell-associated antigens. Thus, CLEC9A functions as a Syk-coupled C-type lectin receptor to mediate sensing of necrosis by the principal DC subset involved in regulating crosspriming to cell-associated antigens.

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Author and article information

Contributors

Xin-Chun Ye: xinchunye@xzhmu.edu.cn

Jin-Xia Hu: jinxia0819@163.com

Gui-Yun Cui: guiyuncui@foxmail.com

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 11 January 2020

Publication date PMC-release: 11 January 2020

Publication date Collection: 2020

Volume: 17

Electronic Location Identifier: 17

Affiliations

[1 ]Institute of Stroke Center and Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, People’s Republic of China

[2 ]Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Xuzhou, People’s Republic of China

[3 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, Department of Neurology, , Drum Tower Hospital, Medical School of Nanjing University, ; Nanjing, People’s Republic of China

[4 ]Department of Rehabilitation Medicine, Linyi Cancer Hospital, Shandong, People’s Republic of China

[5 ]Department of Neurology, Suqian People’s Hospital of Nanjing Drum tower Hospital Group, Suqian, Jiangsu People’s Republic of China

Article

Publisher ID: 1693

DOI: 10.1186/s12974-019-1693-z

PMC ID: 6954534

PubMed ID: 31926564

SO-VID: 30a0b4d6-5b44-475e-a992-9b5be85f5a2f

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 8 November 2019

Date accepted : 26 December 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81971134 and 81571155

Award ID: 81571210 and 81771282

Funded by: Natural Science Foundation of the Higher Education Institutions of Jiangsu Province

Award ID: 17KJB320017

Funded by: FundRef http://dx.doi.org/10.13039/501100013059, Jiangsu Provincial Medical Youth Talent;

Award ID: No. QNRC2016788

Funded by: Suqian Science and Technology Plan

Award ID: S201714

Funded by: FundRef http://dx.doi.org/10.13039/501100004608, Natural Science Foundation of Jiangsu Province;

Award ID: BK20191152

Award ID: BK20150209

Award ID: BL2014031

Funded by: Jiangsu Commission of Heath

Award ID: LGY2019086

Funded by: Xuzhou key research and development program

Award ID: KC18055

Award ID: KC19131

Funded by: Xuzhou Innovation Capacity Building Program

Award ID: KC19239

Funded by: the Summit of Six Top Talents Program of Jiangsu Province

Award ID: 2017-WSN-118

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: dectin-1,syk,inflammation,ischemic stroke

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: dectin-1, syk, inflammation, ischemic stroke

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Dectin-1/Syk signaling triggers neuroinflammation after ischemic stroke in mice

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Abstract

Background

Methods

Results

Conclusion

Related collections

Neuronal Signaling

Most cited references 48

Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.

Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals.

Identification of a dendritic cell receptor that couples sensing of necrosis to immunity

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Cited by 44

Most referenced authors 995