Complement component C3a plays a critical role in endothelial activation and leukocyte recruitment into the brain

Wu, Feifei; Zou, Qiang; Ding, Xiaodan; Shi, Dongyan; Zhu, Xingxing; Hu, Weiguo; Liu, Lixin; Zhou, Hong

doi:10.1186/s12974-016-0485-y

Cited by 78 publications

(50 citation statements)

References 54 publications

(52 reference statements)

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“…Substantial evidence has indicated that certain chemokines and complement components contribute to the recruitment and activation of lymphocytes . Our data indicate that the increased level of CCL5 is induced by PGLYRP2 (Fig.…”

Section: Discussionsupporting

confidence: 61%

Tumor‐Derived Peptidoglycan Recognition Protein 2 Predicts Survival and Antitumor Immune Responses in Hepatocellular Carcinoma

et al. 2020

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Background and Aims Hepatocellular carcinoma (HCC) is linked to immunosuppression. Relieving immunosuppression has been an attractive strategy to improve the efficacy of cancer immunotherapy. Peptidoglycan recognition protein 2 (PGLYRP2) is a pattern recognition receptor which is specifically expressed in liver and implicated in the regulation of innate immunity and immunosurveillance. However, the role of hepatic PGLYRP2 in modulating immune responses against HCC remains to be investigated. Approach and Results In this study, we investigated whether PGLYRP2 is able to influence HCC progression through regulating host antitumor immune responses. We demonstrated that PGLYRP2 was down‐regulated in HCC, which was linked with poor prognosis in patients (P < 0.001). PGLYRP2 overexpression in HCC cells significantly enhanced antitumor immune responses in immune‐competent mice and elevated immune response rates of peripheral blood mononuclear cells against HCC. Mechanistically, DNA methyltransferase 3A–mediated promoter hypermethylation was responsible for the down‐regulation of PGLYRP2 in HCC. PGLYRP2 promoted production of chemokine (C‐C motif) ligand 5 (CCL5) in HCC through binding to the CCL5 promoter, which contributed to the enhanced antitumor immunity. Conclusions We provide evidence that tumor‐derived PGLYRP2 acts as a candidate biomarker for adequate immune response against HCC and improved patient outcomes, indicating the importance of hepatic PGLYRP2 in cancer immunosurveillance and in designing immunotherapeutic approaches.

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Section: Discussionsupporting

confidence: 61%

Tumor‐Derived Peptidoglycan Recognition Protein 2 Predicts Survival and Antitumor Immune Responses in Hepatocellular Carcinoma

et al. 2020

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“…Role of the complement system is also increasingly recognized as contributor to the brain endothelial activation (Wu et al, 2016). Moreover, the critical contribution of microglia to the repair of damaged BBB, which involves mechanisms elicited by purinergic receptor signaling, has been demonstrated recently (Lou et al, 2016).…”

Section: Microvascular/blood Brain Barrier Transcriptome Signaturementioning

confidence: 99%

Microvascular anomaly conditions in psychiatric disease. Schizophrenia – angiogenesis connection

Katsel

Roussos

Pletnikov

et al. 2017

Neuroscience & Biobehavioral Reviews

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Schizophrenia (SZ) is a severe mental disorder with unknown etiology and elusive neuropathological and neurobiological features have been a focus of many theoretical hypotheses and empirical studies. Current genetic and neurobiology information relevant to SZ implicates neuronal developmental and synaptic plasticity abnormalities, and neurotransmitter, microglial and oligodendrocytes dysfunction. Several recent theories have highlighted the neurovascular unit as a potential contributor to the pathophysiology of SZ. We explored the biological plausibility of a link between SZ and the neurovascular system by examining insights gained from genetic, neuroimaging and postmortem studies, which include gene expression and neuropathology analyses. We also reviewed information from animal models of cerebral angiogenesis in order to understand better the complex interplay between angiogenic and neurotrophic factors in development, vascular endothelium/blood brain barrier remodeling and maintenance, all of which contribute to sustaining adequate regional blood flow and safeguarding normal brain function. Microvascular and hemodynamics alterations in SZ highlight the importance of further research and reveal the neurovascular unit as a potential therapeutic target in SZ.

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“…Thus, molecular mechanisms that target endothelial activation could be potential therapeutic targets for CNS inflammation . Blockade of leukocyte adhesion to the endothelium by antibodies or other antagonists has been found to reduce CNS inflammatory conditions . In clinical trials of antileukocyte recruitment therapy, interference with leukocyte‐endothelial interactions by targeting adhesion molecules can relieve chronic inflammation in patients with multiple sclerosis …”

Section: Introductionmentioning

confidence: 99%

Fingolimod targets cerebral endothelial activation to block leukocyte recruitment in the central nervous system

Zhao

Shi

Cao

et al. 2017

Journal of Leukocyte Biology

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Fingolimod (FTY720), an immunomodulator, is approved as an oral treatment for patients with relapsing forms of multiple sclerosis. Its effects are largely attributed to its mechanism of selectively retaining lymphocytes in the lymph nodes to reduce autoreactive T-cell recruitment in the CNS. In this study, we investigated the therapeutic effect of FTY720 on an animal model of CNS inflammation induced by intracerebral ventricle LPS injection. We found that FTY720 treatment significantly prevented LPS-induced neutrophil recruitment in the CNS by inhibiting leukocyte recruitment in cerebral microvessels. Furthermore, FTY720 also inhibited the expressions of adhesion molecules on the cerebral endothelium, but did not affect the expression levels of pro-inflammatory cytokines (TNF-and IL-6) and chemokines (CXCL1 and CXCL2) in the CNS parenchyma. The inhibition of endothelial activation was accompanied by reduced phosphorylation of signaling molecules, including serine/threonine-specific protein kinase (Akt), STAT6, and nuclear factor-B. This FTY720-attenuated inhibition of leukocyte recruitment and endothelial activation was reversed by blocking the functions of sphingosine kinase 2 or sphingosine-1-phosphate receptor 1. Our study demonstrated, for the first time, that FTY720 directly inhibits the phosphorylation of multiple signaling molecules in endothelial cells, thereby effectively blocking leukocyte recruitment in the CNS. K E Y W O R D S

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Complement component C3a plays a critical role in endothelial activation and leukocyte recruitment into the brain

Cited by 78 publications

References 54 publications

Tumor‐Derived Peptidoglycan Recognition Protein 2 Predicts Survival and Antitumor Immune Responses in Hepatocellular Carcinoma

Tumor‐Derived Peptidoglycan Recognition Protein 2 Predicts Survival and Antitumor Immune Responses in Hepatocellular Carcinoma

Microvascular anomaly conditions in psychiatric disease. Schizophrenia – angiogenesis connection

Fingolimod targets cerebral endothelial activation to block leukocyte recruitment in the central nervous system

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