Dataset Information

Porcine Circovirus Type 2 Induces Single Immunoglobulin Interleukin-1 Related Receptor (SIGIRR) Downregulation to Promote Interleukin-1? Upregulation in Porcine Alveolar Macrophage.

ABSTRACT: Multisystemic inflammation in pigs affected by porcine circovirus type 2 (PCV2) indicates the disordered expression of inflammatory cytokines. However, the PCV2-induced expression profile of inflammation cytokines and its regulating mechanism remain poorly understood. In this study, inflammatory cytokines and receptors in porcine alveolar macrophages (PAMs) after PCV2 infection were profiled in vitro by an RT2 ProfilerTM PCR array assay. The regulatory mechanism of interleukin-1? (IL-1?) expression was investigated. Results showed that 49 of 84 inflammation cytokines and receptors were differentially expressed (p < 0.05, absolute fold change ?2) in PAMs at different stages post-PCV2 infection. Moreover, the overexpression of single-immunoglobulin interleukin-1 related receptor (SIGIRR) or the blocking of NF-?B activation by its inhibitor markedly decreased IL-1? secretion. This finding suggested that PCV2-induced overexpression of IL-1? was associated with the downregulation of SIGIRR and the activation of NF-?B. Furthermore, the excessive activity of NF-?B in SIGIRR-knockout PAMs cell line, indicating that SIGIRR negatively regulated IL-1? production by inhibiting the activation of NF-?B. Overall, PCV2-induced downregulation of SIGIRR induction of NF-?B activation is a critical process in enhancing IL-1? production in PAMs. This study may provide insights into the underlying inflammatory response that occurs in pigs following PCV2 infection.

SUBMITTER: Yang S

PROVIDER: S-EPMC6893714 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Porcine Circovirus Type 2 Induces Single Immunoglobulin Interleukin-1 Related Receptor (SIGIRR) Downregulation to Promote Interleukin-1β Upregulation in Porcine Alveolar Macrophage.

Yang Shunli S Liu Baohong B Yin Shuanghui S Shang Youjun Y Zhang Xinming X Khan Muhammad Umar Zafar MUZ Liu Xiangtao X Cai Jianping J

Viruses 20191103 11

Multisystemic inflammation in pigs affected by porcine circovirus type 2 (PCV2) indicates the disordered expression of inflammatory cytokines. However, the PCV2-induced expression profile of inflammation cytokines and its regulating mechanism remain poorly understood. In this study, inflammatory cytokines and receptors in porcine alveolar macrophages (PAMs) after PCV2 infection were profiled in vitro by an RT<sup>2</sup> Profiler<sup>TM</sup> PCR array assay. The regulatory mechanism of interleu ...[more]

PMID: 31684202

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Project description:BackgroundPorcine circovirus type 2 (PCV2) is the causal agent of postweaning multisystemic wasting syndrome (PMWS), which has severely impacted the swine industry worldwide. PCV2 triggers a weak and atypical innate immune response, but the key genes and mechanisms by which the virus interferes with host innate immunity have not yet been elucidated. In this study, genes that control the response of primary porcine alveolar macrophages (PAMs), the main target of PCV2, were profiled in vitro.ResultsPAMs were successfully infected by PCV2-WH strain, as evidenced quantitative real-time polymerase chain reaction (qPCR) and immunofluorescence assay (IFA) results. Infection-related differential gene expression was investigated using pig microarrays from the US Pig Genome Coordination Program and validated by real-time PCR and enzyme-linked immunosorbent assay (ELISA). Microarray analysis at 24 and 48 hours post-infection (HPI) revealed 266 and 175 unique genes, respectively, that were differentially expressed (false discovery rate <0.05; fold-change >2). Only six genes were differentially expressed between 24 and 48 HPI. The up-regulated genes were principally related to immune response, cytokine activity, locomotion, regulation of cell proliferation, apoptosis, cell growth arrest, and antigen procession and presentation. The down-regulated genes were mainly involved in terpenoid biosynthesis, carbohydrate metabolism, translation, proteasome degradation, signal transducer activity, and ribosomal proteins, which were representative of the reduced vital activity of PCV2-infected cells.ConclusionsPCV2 infection of PAMs causes up-regulation of genes related to inflammation, indicating that PCV2 may induce systematic inflammation. PCV2 persistently induced cytokines, mainly through the Toll-like receptor (TLR) 1 and TLR9 pathways, which may promote high levels of cytokine secretion. PCV2 may prevent apoptosis in PAMs by up-regulating SERPINB9 expression, possibly to lengthen the duration of PCV2 replication-permissive conditions. The observed gene expression profile may provide insights into the underlying immunological response and pathological changes that occur in pigs following PCV2 infection.

Project description:Renal cell carcinoma is highly inflamed, and tumor cells are embedded into a microenvironment enriched with IL1. While inflammatory pathways are well characterized in the immune system, less is known about these same pathways in epithelial cells; it is unclear if and how innate immune signals directly impact on cancer cells, and if we could we manipulate these for therapeutic purposes. To address these questions, we first focused on the inflammatory receptors belonging to the IL1- and Toll-like receptor family including negative regulators in a small cohort of 12 clear cell RCC (ccRCC) patients' samples as compared to their coupled adjacent normal tissues. Our data demonstrated that renal epithelial cancer cells showed a specific and distinctive pattern of inflammatory receptor expression marked by a consistent downregulation of the inhibitory receptor SIGIRR mRNA. This repression was confirmed at the protein level in both cancer cell lines and primary tissues. When we analyzed in silico data of different kidney cancer histotypes, we identified the clear cell subtype as the one where SIGIRR was mostly downregulated; nonetheless, papillary and chromophobe tumor types also showed low levels as compared to their normal counterpart. RNA-sequencing analysis demonstrated that IL1 stimulation of the ccRCC cell line A498 triggered an intrinsic signature of inflammatory pathway activation characterized by the induction of distinct "pro-tumor" genes including several chemokines, the autocrine growth factor IL6, the atypical co-transcription factor NFKBIZ, and the checkpoint inhibitor PD-L1. When we looked for the macroareas most represented among the differentially expressed genes, additional clusters emerged including pathways involved in cell differentiation, angiogenesis, and wound healing. To note, SIGIRR overexpression in A498 cells dampened IL1 signaling as assessed by a reduced induction of NFKBIZ. Our results suggest that SIGIRR downregulation unleashes IL1 signaling intrinsic to tumor cells and that manipulating this pathway may be beneficial in ccRCC.

Project description:Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus 2 (PCV2) are economically important pathogens in swine, and pigs with dual infections of PCV2 and PRRSV consistently have more severe clinical symptoms and interstitial pneumonia. However, the synergistic pathogenesis mechanism induced by PRRSV and PCV2 co-infection has not yet been illuminated. Therefore, the aim of this study was to characterize the kinetic changes of immune regulatory molecules, inflammatory factors and immune checkpoint molecules in porcine alveolar macrophages (PAMs) in individuals infected or co-infected with PRRSV and/or PCV2. The experiment was divided into six groups: a negative control group (mock, no infected virus), a group infected with PCV2 alone (PCV2), a group infected with PRRSV alone (PRRSV), a PCV2-PRRSV co-infected group (PCV2-PRRSV inoculated with PCV2, followed by PRRSV 12 h later), a PRRSV-PCV2 co-infected group (PRRSV-PCV2 inoculated with PRRSV, followed by PCV2 12 h later) and a PCV2 + PRRSV co-infected group (PCV2 + PRRSV, inoculated with PCV2 and PRRSV at the same time). Then, PAM samples from the different infection groups and the mock group were collected at 6, 12, 24, 36 and 48 h post-infection (hpi) to detect the viral loads of PCV2 and PRRSV and the relative quantification of immune regulatory molecules, inflammatory factors and immune checkpoint molecules. The results indicated that PCV2 and PRRSV co-infection, regardless of the order of infection, had no effect on promoting PCV2 replication, while PRRSV and PCV2 co-infection was able to promote PRRSV replication. The immune regulatory molecules (IFN-α and IFN-γ) were significantly down-regulated, while inflammatory factors (TNF-α, IL-1β, IL-10 and TGF-β) and immune checkpoint molecules (PD-1, LAG-3, CTLA-4 and TIM-3) were significantly up-regulated in the PRRSV and PCV2 co-infection groups, especially in PAMs with PCV2 inoculation first followed by PRRSV. The dynamic changes in the aforementioned immune molecules were associated with a high viral load, immunosuppression and cell exhaustion, which may explain, at least partially, the underlying mechanism of the enhanced pulmonary lesions by dual infection with PCV2 and PRRSV in PAMs.

Dataset Information

Porcine Circovirus Type 2 Induces Single Immunoglobulin Interleukin-1 Related Receptor (SIGIRR) Downregulation to Promote Interleukin-1? Upregulation in Porcine Alveolar Macrophage.

Publications

Porcine Circovirus Type 2 Induces Single Immunoglobulin Interleukin-1 Related Receptor (SIGIRR) Downregulation to Promote Interleukin-1β Upregulation in Porcine Alveolar Macrophage.

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