Kaposi Sarcoma Herpes Virus (KSHV) infection inhibits macrophage formation and survival by counteracting Macrophage Colony-Stimulating Factor (M-CSF)-induced increase of Reactive Oxygen Species (ROS), c-Jun N-terminal kinase (JNK) phosphorylation and autophagy

Montani, Maria Saveria Gilardini; Falcinelli, Luca; Santarelli, Roberta; Romeo, Maria Anele; Granato, Marisa; Faggioni, Alberto; Cirone, Mara

doi:10.1016/j.biocel.2019.06.008

Cited by 5 publications

(3 citation statements)

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“… 1 KSHV encodes for many proteins homologue to human proteins that favour oncogenesis, counteract apoptosis and subvert immune response such as viral G-protein-coupled receptors (GPCRs), viral Cellular FLICE-inhibitory protein (FLIP) and viral interleukin 6 (IL-6). Among the strategies through which KSHV induces immune suppression there is the impairment of dendritic cell (DC) 2 , 3 essential for anti-tumour immune response 4 or macrophage formation, 5 to dysregulate the release of cytokines by virus-infected DCs 6 or endothelial cells, promoting macrophage polarisation into M2-like/tumour associated macrophage (TAM). 7 Macrophages are plastic cells that can undergo polarisation by shifting between pro-inflammatory M1 and anti-inflammatory M2 functional phenotypes.…”

Section: Introductionmentioning

confidence: 99%

KSHV infection skews macrophage polarisation towards M2-like/TAM and activates Ire1 α-XBP1 axis up-regulating pro-tumorigenic cytokine release and PD-L1 expression

et al. 2020

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Background Kaposi’s Sarcoma Herpesvirus (KSHV) is a gammaherpesvirus strongly linked to human cancer. The virus is also able to induce immune suppression, effect that contributes to onset/progression of the viral-associated malignancies. As KSHV may infect macrophages and these cells abundantly infiltrate Kaposi’s sarcoma lesions, in this study we investigated whether KSHV-infection could affect macrophage polarisation to promote tumorigenesis. Methods FACS analysis was used to detect macrophage markers and PD-L1 expression. KSHV infection and the molecular pathways activated were investigated by western blot analysis and by qRT-PCR while cytokine release was assessed by Multi-analyte Kit. Results We found that KSHV infection reduced macrophage survival and skewed their polarisation towards M2 like/TAM cells, based on the expression of CD163, on the activation of STAT3 and STAT6 pathways and the release of pro-tumorigenic cytokines such as IL-10, VEGF, IL-6 and IL-8. We also found that KSHV triggered Ire1 α-XBP1 axis activation in infected macrophages to increase the release of pro-tumorigenic cytokines and to up-regulate PD-L1 surface expression. Conclusions The findings that KSHV infection of macrophages skews their polarisation towards M2/TAM and that activate Ire1 α-XBP1 to increase the release of pro-tumorigenic cytokines and the expression of PD-L1, suggest that manipulation of UPR could be exploited to prevent or improve the treatment of KSHV-associated malignancies.

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Section: Introductionmentioning

confidence: 99%

KSHV infection skews macrophage polarisation towards M2-like/TAM and activates Ire1 α-XBP1 axis up-regulating pro-tumorigenic cytokine release and PD-L1 expression

et al. 2020

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“…KSHV monocyte infection counteract ROS increase induced by macrophage colony-stimulating factor (M-CSF), preventing JNK and Bcl-2's phosphorylation and inhibiting autophagy. Together with the decrease in TNFa and the increase in the immunosuppressive cytokine IL-10, all these events lead to impaired macrophage survival and differentiation (341). Findings so far allow us to infer that these viruses may induce autophagosomes formation, in which they are transported to the cell surface.…”

Section: Kaposi's Sarcoma Virusmentioning

confidence: 92%

Autophagy in Viral Development and Progression of Cancer

2021

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Autophagy is a complex degradative process by which eukaryotic cells capture cytoplasmic components for subsequent degradation through lysosomal hydrolases. Although this catabolic process can be triggered by a great variety of stimuli, action in cells varies according to cellular context. Autophagy has been previously linked to disease development modulation, including cancer. Autophagy helps suppress cancer cell advancement in tumor transformation early stages, while promoting proliferation and metastasis in advanced settings. Oncoviruses are a particular type of virus that directly contribute to cell transformation and tumor development. Extensive molecular studies have revealed complex ways in which autophagy can suppress or improve oncovirus fitness while still regulating viral replication and determining host cell fate. This review includes recent advances in autophagic cellular function and emphasizes its antagonistic role in cancer cells.

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“…In these cells, the increase of p62/SQSTM1, by leading to a reduction of ROS, impairs the in vitro differentiation of monocytes into dendritic cells (DCs) or macrophages [27]. p62/SQSTM1/NRF2 axis activation may thus represent a strategy exploited by EBV to inhibit the formation of cells, such as DCs, that play a key role in initiating an immune response towards a new antigen [31,32]. From these evidences, it emerges that autophagy and p62/SQSTM1 may represent a link between mTOR and STAT3 activation and NRF2.…”

Section: Nrf2/statinterplay Involves P62/sqstm1 and Autophagymentioning

confidence: 99%

NRF2 and STAT3: friends or foes in carcinogenesis?

et al. 2023

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NRF2 is a transcription factor that plays a pivotal role in carcinogenesis, also through the interaction with several pro-survival pathways. NRF2 controls the transcription of detoxification enzymes and a variety of other molecules impinging in several key biological processes. This perspective will focus on the complex interplay of NRF2 with STAT3, another transcription factor often aberrantly activated in cancer and driving tumorigenesis as well as immune suppression. Both NRF2 and STAT3 can be regulated by ER stress/UPR activation and their cross-talk influences and is influenced by autophagy and cytokines, contributing to shape the microenvironment, and both control the execution of DDR, also by regulating the expression of HSPs. Given the importance of these transcription factors, more investigations aimed at better elucidating the outcome of their networking could help to discover new and more efficacious strategies to fight cancer.

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Kaposi Sarcoma Herpes Virus (KSHV) infection inhibits macrophage formation and survival by counteracting Macrophage Colony-Stimulating Factor (M-CSF)-induced increase of Reactive Oxygen Species (ROS), c-Jun N-terminal kinase (JNK) phosphorylation and autophagy

Cited by 5 publications

References 30 publications

KSHV infection skews macrophage polarisation towards M2-like/TAM and activates Ire1 α-XBP1 axis up-regulating pro-tumorigenic cytokine release and PD-L1 expression

KSHV infection skews macrophage polarisation towards M2-like/TAM and activates Ire1 α-XBP1 axis up-regulating pro-tumorigenic cytokine release and PD-L1 expression

Autophagy in Viral Development and Progression of Cancer

NRF2 and STAT3: friends or foes in carcinogenesis?

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