Epigenetic Regulation of Inflammatory NF-κB Target Genes by IFN-γ via IRF1 DOI Open Access
Bikash Mishra, Claire Wingert, Mahesh Bachu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 2, 2024

Abstract The regulation of inflammatory gene expression involves complex interactions between transcription factors (TFs), signaling pathways and epigenetic chromatin-mediated mechanisms. This study investigated mechanisms by which IFN-γ-mediated priming augments TLR-induced NF-κB target genes in primary human monocytes. IFN-γ enhanced the signature such as IL6 , TNF IL1B CXCL10 when monocytes were exposed to various TLR agonists. RNA-seq analysis identified synergistically activated LPS, enriched pathways. Similar synergistic activation was observed with TLR1/2 agonist PAM3CYS, suggesting a shared regulatory mechanism. ATAC-seq revealed that ligands induce IRF1 TF activity independently IFN-γ. JAK1/2 inhibitor (iJAK) treatment reduced protein levels, especially IFN-γ-treated monocytes, but not LPS-stimulated LPS-induced may compensate for loss IFN-γ-induced IRF1. We applied CRISPR-Cas9 knock out found abrogates key genes, pivotal role genetic data corroborated CUT&RUN showing resistance binding JAK inhibition under (IFN-γ + LPS) costimulated conditions, co-occupancy sites NF-κB. enhances our understanding regulation, highlighting player potential therapeutic diseases.

Language: Английский

IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms DOI
Bikash Mishra, Mahesh Bachu, Ruoxi Yuan

et al.

Nature Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

Language: Английский

Citations

1
Emerging concepts and treatments in autoinflammatory interferonopathies and monogenic systemic lupus erythematosus DOI
Raphaela Goldbach‐Mansky, Sara Alehashemi, Adriana A. de Jesus

et al.

Nature Reviews Rheumatology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 2, 2024

Language: Английский

Citations

4
Opposing Regulation of TNF Responses and IL-1β+ Macrophages by PGE2-cAMP and IFN-γ Signaling DOI Open Access
Upneet K. Sokhi, Bikash Mishra, Ruoxi Yuan

et al.

Published: March 4, 2025

IL-1β-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory (ICI-arthritis), and pancreatic cancer proposed to be pathogenic. In RA IL-1β+ express a TNF+PGE2 (TP) gene expression signature induced by cooperation between PGE2 TNF signaling, but mechanisms that induce these cells the extent which they contribute arthritic phenotypes are not known. this study we used an integrated transcriptomic epigenomic analysis primary human monocytes PGE2-TNF crosstalk, how it is regulated IFN-γ, as occurs synovial macrophages. We identified (TNF + PGE2)- enriched IL1β+ macrophage subset defined scRNAseq includes genes pathogenic IL-1, Notch neutrophil chemokine pathways. A similar was apparent newly ICI-arthritis. TP distinct from canonical NF-κB target such , IL6 IL12B activated of PGE2-induced AP-1, CEBP NR4A family transcription factors with TNF-induced activity. Unexpectedly, IFN-γ suppressed induction activity ablate genes, while promoting T cell chemokines like CXCL10. These results reveal basis for synergistic TNF, novel regulatory axis whereby oppose each other determine balance two programs relevant

Language: Английский

Citations

0
Opposing Regulation of TNF Responses and IL-1β+ Macrophages by PGE2-cAMP and IFN-γ Signaling DOI Open Access
Upneet K. Sokhi, Bikash Mishra, Ruoxi Yuan

et al.

Published: March 4, 2025

IL-1β-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory (ICI-arthritis), and pancreatic cancer proposed to be pathogenic. In RA IL-1β+ express a TNF+PGE2 (TP) gene expression signature induced by cooperation between PGE2 TNF signaling, but mechanisms that induce these cells the extent which they contribute arthritic phenotypes are not known. this study we used an integrated transcriptomic epigenomic analysis primary human monocytes PGE2-TNF crosstalk, how it is regulated IFN-γ, as occurs synovial macrophages. We identified (TNF + PGE2)- enriched IL1β+ macrophage subset defined scRNAseq includes genes pathogenic IL-1, Notch neutrophil chemokine pathways. A similar was apparent newly ICI-arthritis. TP distinct from canonical NF-κB target such , IL6 IL12B activated of PGE2-induced AP-1, CEBP NR4A family transcription factors with TNF-induced activity. Unexpectedly, IFN-γ suppressed induction activity ablate genes, while promoting T cell chemokines like CXCL10. These results reveal basis for synergistic TNF, novel regulatory axis whereby oppose each other determine balance two programs relevant

Language: Английский

Citations

0
Deconvoluting the interplay of innate and adaptive immunity in BCG-induced nonspecific and TB-specific host resistance DOI Open Access
Kerry L. Hilligan, Patricia A. Darrah, Robert A. Seder

et al.

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(4)

Published: Feb. 28, 2025

BCG is the oldest vaccine in continuous use. While current intradermal vaccination regimens confer limited protection outside context of pediatric extrapulmonary tuberculosis (TB), promising new data indicate that when administered mucosally or intravenously at a higher dose, can induce sterilizing immunity against pulmonary TB nonhuman primates. also known to promote nonspecific host resistance variety unrelated infections and standard immunotherapy for bladder cancer, suggesting this innate immune function may contribute its protective role TB. Here, we propose both mycobacterial-specific off-target effects depend on interplay adaptive cells cytokines they produce, elucidation interaction should be major strategy development more effective BCG-based vaccines immunotherapies.

Language: Английский

Citations

0
Elucidating the chromatin-driven transcription regulatory networks response to Streptococcus agalactiae infection under low temperature in Nile tilapia DOI
Songqian Huang, Wenxin Zhao, C. Yan

et al.

Fish & Shellfish Immunology, Journal Year: 2025, Volume and Issue: 164, P. 110464 - 110464

Published: May 27, 2025

Language: Английский

Citations

0
The distinct transcriptomic signature of the resolution phase fibroblast-like synoviocytes supports endothelial cell dysfunction DOI Creative Commons
Surabhi Gautam, J. A. Whittaker, Rushi Vekariya

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: May 30, 2025

Patients suffering from rheumatoid arthritis (RA) and related autoimmune joint diseases exhibit cyclic episodes of resolution exacerbation inflammation, referred to as flares. Fibroblast-like synoviocytes (FLSs) that are epigenetically transformed by chronic inflammation implicated the orchestrators these In this study, we compared cellular molecular features FLSs during inflammatory phases RA progression. We performed histopathological evaluations joints an inducible tumor necrosis factor-alpha (TNF-α) transgenic mouse model reveal phenotypic hallmarks including synovial hyperplasia, increased angiogenesis, macrophage infiltration, were all reversed upon initiation resolution. However, phase exhibited a transcriptomic signature reminiscent highly state. They G0/G1 cell cycle arrest accompanied reduced viability. addition, factors secreted FLSs, induced death, decreased angiogenic potential in human microvascular umbilical cord endothelial cells. These findings indicate secretome impairs function suggest understanding interaction between cells is essential for achieving complete remission.

Language: Английский

Citations

0
Innate immunity—With an adaptive twist DOI
Steven Z. Josefowicz, Joseph C. Sun

Immunological Reviews, Journal Year: 2024, Volume and Issue: 323(1), P. 5 - 7

Published: April 17, 2024

Language: Английский

Citations

1
The Protective Role of Transcription Factor Nrf2 in Murine Macrophage Activation Syndrome DOI
Paul M. Gallo,

E V Elliott,

G. C. Ford

et al.

Journal of Leukocyte Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 10, 2024

Macrophage activation syndrome (MAS) is characterized by multi-lineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. Transcription factor Nrf2 a master regulator of redox homeostasis. In this work we aim to investigate the role in murine hyperinflammation mechanisms which red blood cell products regulates pro-inflammatory cytokine production.

Language: Английский

Citations

0
Opposing Regulation of TNF Responses and IL-1β+ Macrophages by PGE2-cAMP and IFN-γ Signaling DOI Creative Commons
Upneet K. Sokhi, Ruoxi Yuan, Bikash Mishra

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 12, 2024

Abstract IL-1β-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory (ICI-arthritis), and pancreatic cancer proposed to be pathogenic. In RA IL-1β+ express genes cooperatively induced by PGE2 TNF signaling, but mechanisms that induce these cells the extent which they contribute arthritic phenotypes are not known. this study we used an integrated transcriptomic epigenomic analysis primary human monocytes PGE2-TNF crosstalk, how it is regulated IFN-γ, as occurs synovial macrophages. We identified a + (TP) gene expression signature enriched previously IL1β+ monocytic subset defined scRNAseq includes pathogenic IL-1, Notch neutrophil chemokine pathways. A similar TP was apparent macrophage newly ICI-arthritis. Reference mapping revealed ICI-arthritis myeloid map primarily onto four clusters, extends beyond subsets of adjacent suggestive new functional monocyte subset. distinct from canonical NF-κB target such , IL6 IL12B activated cooperation PGE2-induced AP-1, CEBP NR4A family transcription factors with TNF-induced activity. Unexpectedly, IFN-γ suppressed induction activity ablate genes, while promoting T cell chemokines like CXCL10. The opposing cross-regulation IFN signaling vitro reflected vivo mutually exclusive signatures different clusters monocytes. These results reveal basis for synergistic TNF, novel regulatory axis whereby oppose each other determine balance between two programs relevant

Language: Английский

Citations

0