Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection

Luo, Huanle; Winkelmann, E.; Zhu, Shuang; Ru, Wenjuan; Mays, Elizabeth; Silvas, Jesus A.; Vollmer, Lauren L.; Gao, Junling; Peng, Bi Hung; Bopp, Nathen E.; Cromer, Courtney; Shan, Chao; Xie, Guorui; Li, Guangyu; Tesh, Robert B.; Popov, Vsevolod L.; Shi, Pei Yong; Sun, Shao‐Cong; Wu, Ping; Klein, Robyn S.; Tang, Shuang; Zhang, Wenbo; Aguilar, Patricia V.; Wang, Tian

doi:10.1172/jci99902

Cited by 33 publications

(34 citation statements)

References 57 publications

(83 reference statements)

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“…On the contrary, a previous study proposed that Peli1-deficient mice resulted in reduced viral loads in tissues and attenuated brain inflammation in EAE [29]. Another study conducted by Luo et al [20] also found that upon intranasal infection with vascular stomatitis virus (VSV), the Peli1-deficient mice displayed with reduced brain viral titer and increased survival rate in the central nervous system (CNS) [19]. However, whether Peli1 is associated with the development of autoimmune POI has yet to be explored.…”

Section: Discussionmentioning

confidence: 95%

“…Peli1 has been reported to be abundantly expressed in T lymphocytes and functions as a negative regulator in T cell activation. It is associated with multiple autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and autoimmune encephalomyelitis (EAE) [19][20][21]. The overexpression of Peli1 led to improved self-tolerance and immunosuppression.…”

Section: Introductionmentioning

confidence: 99%

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miR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency

Xie

Wang

et al. 2020

Journal of Immunology Research

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Background. Premature ovarian insufficiency (POI) represents the hypergonadotropic hypoestrogenic symptoms that result in the loss of ovarian follicles. 5-30% POI cases are suggested to be involved in autoimmune etiology. MicroRNA-21 (miR-21) plays a vital role in ovarian folliculogenesis via regulating and interacting with multiple target genes. Here, we conduct the target prediction of miR-21, identify the expression and correlation of miR-21 and its putative target Pellino-1 (Peli1), and confirm their relationship with clinical characteristics in autoimmune POI. Methods. Bioinformatic analysis was conducted to screen the miR-21 putative target gene. Autoimmune POI mouse models were established by ZP3 immunization. Serum miR-21, Peli1 mRNA of peripheral blood mononuclear cells (PBMCs) and regulatory T cells (Tregs), general status, spleen Tregs ratio, inflammatory factors, ovarian endocrine function, and ovarian structure were evaluated. For autoimmune POI patients, serum miR-21, PBMCs Peli1 mRNA levels, general data, immune parameters, hormone levels, and ultrasound examinations were obtained. The correlations of miR-21 with Peli1 and clinical characteristics in patients were analyzed. Results. Peli1 was selected based on four microRNA prediction databases and literature retrieval. In mouse models, serum miR-21 level, PBMCs and Tregs Peli1 mRNA, and spleen Tregs ratio were 0.61±0.09, 0.12±0.12, 0.27±0.23 and 4.82±0.58, respectively, lower than those in the control group. In patients, miR-21 level (0.60±0.14) and Peli1 mRNA (0.30±0.14) were lower than those in the control group (1.01±0.07 and 1.63±0.54); miR-21 was positively related with Peli1, AMH, E2, the size of the uterus, and ovarian volume and negatively related with FSH, LH, and the number of positive immune parameters (AOAb, EMAb, ACL, ANA, ds-DNA, ACA, IgG, IgA, IgM, IgE, C3, and C4). Conclusions. Low expressions of miR-21 and Peli1 were detected in autoimmune POI mice and patients. Positive correlation between miR-21 and Peli1 was observed in autoimmune POI patients, suggesting that miR-21 and Peli1 might be associated with the pathogenesis of autoimmune POI.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

miR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency

Xie

Wang

et al. 2020

Journal of Immunology Research

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“…Peli1 also modulates necroptosis and apoptosis [58]. In a recent report [59], we demonstrated that Peli1 promotes lethal viral encephalitis by facilitating WNV replication in neurons and microglia and induction of neuroinflammation. It is likely that Peli1 contributes to neuron death directly by promoting WNV replication and indirectly by induction of neuroinflammation.…”

Section: Ubiquitination Proteinsmentioning

confidence: 87%

West Nile Virus Induced Cell Death in the Central Nervous System

Peng

2019

Pathogens

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West Nile virus (WNV), a mosquito-borne, single-stranded flavivirus, has caused annual outbreaks of viral encephalitis in the United States since 1999. The virus induces acute infection with a clinical spectrum ranging from a mild flu-like febrile symptom to more severe neuroinvasive conditions, including meningitis, encephalitis, acute flaccid paralysis, and death. Some WNV convalescent patients also developed long-term neurological sequelae. Neither the treatment of WNV infection nor an approved vaccine is currently available for humans. Neuronal death in the central nervous system (CNS) is a hallmark of WNV-induced meningitis and encephalitis. However, the underlying mechanisms of WNV-induced neuronal damage are not well understood. In this review, we discuss current findings from studies of WNV infection in vitro in the CNS resident cells and the in vivo animal models, and provide insights into WNV-induced neuropathogenesis.

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“…Peli is a newly identified family of E3 ubiquitin ligases, including Peli1, Peli2, and Peli3 [46]. Specifically, Peli1 is emerging as a microglia-specific regulator to participate in the pathophysiological process of experimental autoimmune encephalomyelitis (EAE) [19], subarachnoid hemorrhage (SHA) [24], and West Nile virus (WNV) encephalitis [23]. However, the possible role of Peli1 in neuropathic pain is not explored briefly.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Peli1 is required for ubiquitination of substrate proteins such as TRAF6 to regulate NF-κB activation and MAPK signaling [21,22]. Moreover, Peli1 is emerging as a microglia-specific regulator to participate in the pathophysiological process of experimental autoimmune encephalomyelitis (EAE) [19], West Nile virus (WNV) encephalitis [23], and subarachnoid hemorrhage (SHA) [24], suggesting causative involvement of Peli1 in neuroinflammation. However, it is unclear whether Peli1 would modulate spinal neuroinflammation in neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord

Wang

Chen

Liu

et al. 2020

J Neuroinflammation

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Background: Spinal cord microglia plays a crucial role in the pathogenesis of neuropathic pain. However, the mechanisms underlying spinal microglial activation during neuropathic pain remain incompletely determined. Here, we investigated the role of Pellino1 (Peli1) and its interplay with spinal microglial activation in neuropathic pain. Methods: In this study, we examined the effects of Peli1 on pain hypersensitivity and spinal microglial activation after chronic constriction injury (CCI) of the sciatic nerve in mice. The molecular mechanisms involved in Peli1mediated hyperalgesia were determined by western blot, immunofluorescence, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). We utilized immunoprecipitation to examine the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) following CCI. In addition, we explored the effect of Peli1 on BV2 microglial cells in response to lipopolysaccharide (LPS) challenge. Results: We found that CCI induced a significant increase in the levels of Peli1, which was present in the great majority of microglia in the spinal dorsal horn. Our results showed that spinal Peli1 contributed to the induction and maintenance of CCI-induced neuropathic pain. The biochemical data revealed that CCI-induced Peli1 in the spinal cord significantly increased mitogen-activated protein kinase (MAPK) phosphorylation, activated nuclear factor kappa B (NF-κB), and enhanced the production of proinflammatory cytokines, accompanied by spinal microglial activation. Peli1 additionally was able to promote K63-linked ubiquitination of TRAF6 in the ipsilateral spinal cord following CCI. Furthermore, we demonstrated that Peli1 in microglial cells significantly enhanced inflammatory reactions after LPS treatment. Conclusion: These results suggest that the upregulation of spinal Peli1 is essential for the pathogenesis of neuropathic pain via Peli1-dependent mobilization of spinal cord microglia, activation of MAPK/NF-κB signaling, and production of proinflammatory cytokines. Modulation of Peli1 may serve as a potential approach for the treatment of neuropathic pain.

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Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection

Cited by 33 publications

References 57 publications

miR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency

miR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency

West Nile Virus Induced Cell Death in the Central Nervous System

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord

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