SMRT and NCoR1 fine-tune inflammatory versus tolerogenic balance in dendritic cells by differentially regulating STAT3 signaling
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Evaluation Summary:
This paper is of interest to immunologists studying the transcriptional control of innate immune responses. The paper presents a new role for transcriptional regulators in the control of inflammatory properties of cross-presenting dendritic cells that are involved in anti-tumoral and anti-viral immunity. The data support the conclusions but some modifications of the text and additional experiments are required.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance is unexplored. NCoR1-mediated repression of DC immune-tolerance has been recently reported. Here we found that depletion of NCoR1 paralog SMRT (NCoR2) enhanced cDC1 activation and expression of IL-6, IL-12 and IL-23 while concomitantly decreasing IL-10 expression/secretion. Consequently, co-cultured CD4 + and CD8 + T-cells depicted enhanced Th1/Th17 frequency and cytotoxicity, respectively. Comparative genomic and transcriptomic analysis demonstrated differential regulation of IL-10 by SMRT and NCoR1. SMRT depletion represses mTOR-STAT3-IL10 signaling in cDC1 by down-regulating NR4A1. Besides, Nfkbia and Socs3 were down-regulated in Ncor2 ( Smrt ) depleted cDC1, supporting increased production of inflammatory cytokines. Moreover, studies in mice showed, adoptive transfer of SMRT depleted cDC1 in OVA-DTH induced footpad inflammation led to increased Th1/Th17 and reduced tumor burden after B16 melanoma injection by enhancing oncolytic CD8 + T-cell frequency, respectively. We also depicted decreased Ncor2 expression in Rheumatoid Arthritis, a Th1/Th17 disease.
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Evaluation Summary:
This paper is of interest to immunologists studying the transcriptional control of innate immune responses. The paper presents a new role for transcriptional regulators in the control of inflammatory properties of cross-presenting dendritic cells that are involved in anti-tumoral and anti-viral immunity. The data support the conclusions but some modifications of the text and additional experiments are required.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Dendritic cells are pivotal in the regulation of the balance between tolerance and inflammation. The transcriptional mechanisms that regulate this balance remain poorly understood. Raghav et al investigated the role of the transcriptional co-repressors SMRT and NCoR1 in the activation of conventional type I dendritic cells (cDC1) by Toll-like receptor agonists using in vitro cell model, flow cytometry and genomic analysis. The authors found that SMRT limits the activation of DC1 and the expression of inflammatory cytokines driving CD8 and CD4 T helper cells responses while supporting the expression of the anti-inflammatory IL-10. Thorough and well-presented genomic analyses reveal interesting similarities and differences in the control of genes expression by two paralogs NCOR1 and SMRT during immune …
Reviewer #1 (Public Review):
Dendritic cells are pivotal in the regulation of the balance between tolerance and inflammation. The transcriptional mechanisms that regulate this balance remain poorly understood. Raghav et al investigated the role of the transcriptional co-repressors SMRT and NCoR1 in the activation of conventional type I dendritic cells (cDC1) by Toll-like receptor agonists using in vitro cell model, flow cytometry and genomic analysis. The authors found that SMRT limits the activation of DC1 and the expression of inflammatory cytokines driving CD8 and CD4 T helper cells responses while supporting the expression of the anti-inflammatory IL-10. Thorough and well-presented genomic analyses reveal interesting similarities and differences in the control of genes expression by two paralogs NCOR1 and SMRT during immune activation in DC1. The paper presents a new regulatory circuit supporting the transcriptional regulation of IL-10 after TLR stimulation in cDC1.
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Reviewer #2 (Public Review):
NCOR/SMRT corepressor complexes control inflammation and their dysregulation has been reported to be of clinical importance. In this manuscript, the authors studied SMRT in dentritic cells. The authors propose that SMRT KD enhances DC inflammatory activation while reduces IL10 expression, which shows similarity with macrophages, a relatively close innate immune cell type. The authors propose the underlying mechanisms related with Nur-77, mTOR and STAT3, that SMRT KD downregulates Nur-77 and thereby inhibits the mTOR/STAT3 axis, leading to decreased IL10. The authors used multi-OMICs approaches along with several functional experiments and clinical evidence to support the relevance of SMRT regulated dentritic cells in inflammatory diseases and cancer. The findings reveal the so far unclear functions and …
Reviewer #2 (Public Review):
NCOR/SMRT corepressor complexes control inflammation and their dysregulation has been reported to be of clinical importance. In this manuscript, the authors studied SMRT in dentritic cells. The authors propose that SMRT KD enhances DC inflammatory activation while reduces IL10 expression, which shows similarity with macrophages, a relatively close innate immune cell type. The authors propose the underlying mechanisms related with Nur-77, mTOR and STAT3, that SMRT KD downregulates Nur-77 and thereby inhibits the mTOR/STAT3 axis, leading to decreased IL10. The authors used multi-OMICs approaches along with several functional experiments and clinical evidence to support the relevance of SMRT regulated dentritic cells in inflammatory diseases and cancer. The findings reveal the so far unclear functions and mechanisms of corepressor-based dentritic cell (and T cells) regulation, and is important and interesting.
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