Human Cytomegalovirus Interleukin-10 Polarizes Monocytes toward a Deactivated M2c Phenotype To Repress Host Immune Responses

Avdic, Selmir; Cao, John Z.; McSharry, Brian P.; Clancy, Leighton; Brown, Rebecca T.; Steain, Megan; Gottlieb, David; Abendroth, Allison; Slobedman, Barry

doi:10.1128/jvi.00912-13

Cited by 71 publications

(70 citation statements)

References 50 publications

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“…The timing of this upregulation is comparable to that of the upregulation of hIL-10 transcription by hIL-10 protein (39) and so not only highlights the rapid nature of cmvIL-10-mediated upregulation of hIL-10 mRNA transcription but also suggests that cmvIL-10 may act as a catalyst to drive hIL-10-mediated upregulation of hIL-10. However, while cmvIL-10 may amplify its immunomodulatory impact by upregulating hIL-10, it does not absolutely require hIL-10 to function as cmvIL-10 remained capable of upregulating cell surface CD163, a scavenger receptor expressed at high levels on hIL-10-induced, deactivated M2 monocytes/macrophages (23,40,41), even when hIL-10 was neutralized. Thus, cmvIL-10 appears to be capable of functioning both directly and indirectly and in doing so may provide more than one opportunity for HCMV to suppress host immune function(s).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the engagement of hIL-10R, we show that functional HO-1, a heme-degrading enzyme with immunosuppressive functions (31), is also required for cmvIL-10-mediated upregulation of hIL-10. We previously reported that HO-1 is upregulated in CD14 ϩ monocytes treated with recombinant viral IL-10 protein or by treatment with supernatant from cells infected with parental virus but not by treatment with supernatant from cells infected with a viral IL-10 deletion virus (23). Our current work shows that cmvIL-10-mediated upregulation of HO-1 in CD14 ϩ monocytes requires binding of cmvIL-10 to hIL-10R and that this HO-1 upregulation is important for the upregulation of hIL-10.…”

Section: Discussionmentioning

confidence: 99%

“…Flow cytometry for cell surface proteins was performed as per a previously published protocol (23). Antibodies used in this study were mouse anti-human CD163-phycoerythrin (PE) (BD Biosciences) with a corresponding isotype control.…”

Section: Treatment Of Cd14mentioning

confidence: 99%

“…Total RNA was extracted from CD14 ϩ monocytes using an innuPREP RNA minikit (Analytik-Jena) prior to cDNA synthesis using an AffinityScript cDNA synthesis kit (Agilent Technologies). Reaction mixtures were set up using Brilliant II SYBR Green quantitative PCR (QPCR) master mix (Agilent Technologies), and changes in mRNA expression levels were measured by quantitative reverse transcription-PCR (qRT-PCR) (StepOne Plus; Applied Biosystems) as per a previously published protocol (23). The following primers were used in this study: glyceraldehyde-3-phosphate dehydrogenase forward primer (GAPDH-F), 5=-TCACCAGGGCTGCTTTTAAC-3=; GAPDH reverse (GAPDH-R), 5=-GACAAGCTTCCCGTTCTCAG-3=; hIL-10-F, 5=-GCCTAACATGCT TCGAGATC-3=; hIL-10-R, 5=-TGATGTCTGGGTCTTGGTTC-3=; dual-specificity phosphatase 1 (DUSP1)-F, 5=-CTGCCTTGATCAAC GTCTCA-3=; DUSP1-R, 5=-ACCCTTCCTCCAGCATTCTT-3=; tumor progression locus 2 (TPL2)-F, 5=-TTCCGATGTTCTCCTGATCC-3=; TPL2-R, 5=-CAGTTTCACCCCACAGGACT-3=.…”

Section: Treatment Of Cd14mentioning

confidence: 99%

“…In addition, treatment of CD14 ϩ monocytes with either a mixture of recombinant cmvIL-10 and LAcmvIL-10 proteins (termed viral IL-10) or with supernatants from permissive human foreskin fibroblasts (HFFs) infected with parental or UL111A deletion viruses has demonstrated that the UL111A gene products skew monocyte polarization toward a deactivated M2c phenotype that significantly reduces CD4 ϩ T cell activation and proliferation (23). Interestingly, LAcmvIL-10 increases hIL-10 secretion by CD14 ϩ monocytes, suggesting that this viral cytokine may amplify its biological impact via modulation of hIL-10 (24).…”

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confidence: 99%

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Human Cytomegalovirus-Encoded Human Interleukin-10 (IL-10) Homolog Amplifies Its Immunomodulatory Potential by Upregulating Human IL-10 in Monocytes

Avdic

McSharry

Steain

et al. 2016

J Virol

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The human cytomegalovirus (HCMV) gene UL111A encodes cytomegalovirus-encoded human interleukin-10 (cmvIL-10), a homolog of the potent immunomodulatory cytokine human interleukin 10 (hIL-10). This viral homolog exhibits a range of immunomodulatory functions, including suppression of proinflammatory cytokine production and dendritic cell (DC) maturation, as well as inhibition of major histocompatibility complex (MHC) class I and class II. Here, we present data showing that cmvIL-10 upregulates hIL-10, and we identify CD14؉ monocytes and monocyte-derived macrophages and DCs as major sources of hIL-10 secretion in response to cmvIL-10. Monocyte activation was not a prerequisite for cmvIL-10-mediated upregulation of hIL-10, which was dose dependent and controlled at the transcriptional level. Furthermore, cmvIL-10 upregulated expression of tumor progression locus 2 (TPL2), which is a regulator of the positive hIL-10 feedback loop, whereas expression of a negative regulator of the hIL-10 feedback loop, dual-specificity phosphatase 1 (DUSP1), remained unchanged. Engagement of the hIL-10 receptor (hIL-10R) by cmvIL-10 led to upregulation of heme oxygenase 1 (HO-1), an enzyme linked with suppression of inflammatory responses, and this upregulation was required for cmvIL-10-mediated upregulation of hIL-10. We also demonstrate an important role for both phosphatidylinositol 3-kinase (PI3K) and STAT3 in the upregulation of HO-1 and hIL-10 by cmvIL-10. In addition to upregulating hIL-10, cmvIL-10 could exert a direct immunomodulatory function, as demonstrated by its capacity to upregulate expression of cell surface CD163 when hIL-10 was neutralized. This study identifies a mechanistic basis for cmvIL-10 function, including the capacity of this viral cytokine to potentially amplify its immunosuppressive impact by upregulating hIL-10 expression. IMPORTANCEHuman cytomegalovirus (HCMV) is a large, double-stranded DNA virus that causes significant human disease, particularly in the congenital setting and in solid-organ and hematopoietic stem cell transplant patients. A prominent feature of HCMV is the wide range of viral gene products that it encodes which function to modulate host defenses. One of these is cmvIL-10, which is a homolog of the potent immunomodulatory cytokine human interleukin 10 (hIL-10). In this study, we report that, in addition to exerting a direct biological impact, cmvIL-10 upregulates the expression of hIL-10 by primary blood-derived monocytes and that it does so by modulating existing cellular pathways. This capacity of cmvIL-10 to upregulate hIL-10 represents a mechanism by which HCMV may amplify its immunomodulatory impact during infection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Treatment Of Cd14mentioning

confidence: 99%

Section: Treatment Of Cd14mentioning

confidence: 99%

mentioning

confidence: 99%

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Human Cytomegalovirus-Encoded Human Interleukin-10 (IL-10) Homolog Amplifies Its Immunomodulatory Potential by Upregulating Human IL-10 in Monocytes

Avdic

McSharry

Steain

et al. 2016

J Virol

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Cytomegalovirus latency and reactivation: recent insights into an age old problem

Dupont

Reeves

2015

Reviews in Medical Virology

159

156

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Human cytomegalovirus (HCMV) infection remains a major cause of morbidity in patient populations. In certain clinical settings, it is the reactivation of the pre-existing latent infection in the host that poses the health risk. The prevailing view of HCMV latency was that the virus was essentially quiescent in myeloid progenitor cells and that terminal differentiation resulted in the initiation of the lytic lifecycle and reactivation of infectious virus. However, our understanding of HCMV latency and reactivation at the molecular level has been greatly enhanced through recent advancements in systems biology approaches to perform global analyses of both experimental and natural latency. These approaches, in concert with more classical reductionist experimentation, are furnishing researchers with new concepts in cytomegalovirus latency and suggest that latent infection is far more active than first thought. In this review, we will focus on new studies that suggest that distinct sites of cellular latency could exist in the human host, which, when coupled with recent observations that report different transcriptional programmes within cells of the myeloid lineage, argues for multiple latent phenotypes that could impact differently on the biology of this virus in vivo. Finally, we will also consider how the biology of the host cell where the latent infection persists further contributes to the concept of a spectrum of latent phenotypes in multiple cell types that can be exploited by the virus.

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Protective and pathological roles of regulatory immune cells in human cytomegalovirus infection following hematopoietic stem cell transplantation

Namdari

Hosseini

Yazdanifar

et al. 2021

Reviews in Medical Virology

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Human cytomegalovirus (HCMV) is ubiquitously prevalent. Immune system in healthy individuals is capable of controlling HCMV infection; however, HCMV can be life-threatening for immunocompromised individuals, such as transplant recipients. Both innate and adaptive immune systems are critically involved in the HCMV infection. Recent studies have indicated that regulatory immune cells which play essential roles in maintaining a healthy immune environment are closely related to immune response in HCMV infection. However, the exact role of regulatory immune cells in immune regulation and homoeostasis during the battle between HCMV and host still requires further research. In this review, we highlight the protective and pathological roles of regulatory immune cells in HCMV infection following hematopoietic stem cell transplantation (HSCT).

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Human Cytomegalovirus Interleukin-10 Polarizes Monocytes toward a Deactivated M2c Phenotype To Repress Host Immune Responses

Cited by 71 publications

References 50 publications

Human Cytomegalovirus-Encoded Human Interleukin-10 (IL-10) Homolog Amplifies Its Immunomodulatory Potential by Upregulating Human IL-10 in Monocytes

Human Cytomegalovirus-Encoded Human Interleukin-10 (IL-10) Homolog Amplifies Its Immunomodulatory Potential by Upregulating Human IL-10 in Monocytes

Cytomegalovirus latency and reactivation: recent insights into an age old problem

Protective and pathological roles of regulatory immune cells in human cytomegalovirus infection following hematopoietic stem cell transplantation

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