Biology subjects

Ivashkiv, L.

Publications and source records attributed to Ivashkiv, L..

4 recordsLinked to original sources

bioRxiv2024

IL-10 Targets IRFs to Suppress IFN and Inflammatory Response Genes by Epigenetic Mechanisms

Interleukin-10 (IL-10) is pivotal in suppressing inflammation and innate immune activation, in large part by suppressing induction of genes by potent inflammatory factors such as TLR ligands. Despite decades of research, molecular mechanisms underlying this inhibition have not been resolved. This study utilized an integrated epigenomic analysis of gene transcription, chromatin accessibility, histone modifications and transcription factor binding to investigate IL-10-mediated suppression of LPS and TNF responses in primary human monocytes. Instead of inhibiting core TLR4-activated pathways such as NF-{kappa}B, MAPK-AP-1 and TBK1-IRF3 signaling, IL-10 targeted IRF transcription factor activity and DNA binding, particularly IRF5 and an IRF1-mediated amplification loop that is operative in monocytes. This resulted in suppression of inflammatory NF-{kappa}B target genes, in whose activation IRFs play an amplifying role, and near-complete suppression of interferon-stimulated genes. Mechanisms of TLR4 and TNFR target gene inhibition included downregulation of chromatin accessibility, de novo enhancer formation, and IRF1-associated H3K27ac activating histone marks. These results provide a mechanism by which IL-10 suppresses inflammatory NF-{kappa}B target genes, highlight the role of IRF1 in inflammatory gene expression, and describe an underappreciated suppression of IFN responses by epigenetic mechanisms.

immunology↗

bioRxiv2024

Langerhans cells regulate immunity in adulthood by regulating postnatal dermal lymphatic development

The communication between skin and draining lymph nodes is crucial for well-regulated immune responses to skin insults. The skin sends antigen and other signals via lymphatic vessels to regulate lymph node activity, and regulating dermal lymphatic function is another means to control immunity. Here, we show that Langerhans cells (LCs), epidermis-derived antigen-presenting cells, mediate dermal lymphatic expansion and phenotype acquisition postnatally, a function is independent of LC entry into lymphatic vessels. This postnatal LC-lymphatic axis serves in part to control inflammatory systemic T cell responses in adulthood. Our data provide a tissue-based mechanism by which LCs regulate T cells remotely across time and space and raise the possibility that immune diseases in adulthood could reflect compromise of the LC-lymphatic axis in childhood.

immunology↗

bioRxiv2023

Staphyloccocus aureus biofilm, in the absence of planktonic bacteria, produces factors that activate counterbalancing inflammatory and immune-suppressive genes in human monocytes

Staphyloccocus aureus (S. aureus) is a major bacterial pathogen in orthopedic periprosthetic joint infection (PJI). S. aureus forms biofilms that promote persistent infection by shielding bacteria from immune cells and inducing an antibiotic-resistant metabolic state. We developed an in vitro system to study S. aureus biofilm interactions with primary human monocytes in the absence of planktonic bacteria. In line with previous in vivo data, S. aureus biofilm induced expression of inflammatory genes such as TNF and IL1B, and their anti-inflammatory counter-regulator IL-10. S. aureus biofilm also activated expression of PD-1 ligands that suppress T cell function, and of IL-1RA that suppresses differentiation of protective Th17 cells. Gene induction did not require monocyte:biofilm contact and was mediated by a soluble factor(s) produced by biofilm-encased bacteria that was heat resistant and > 3 kD in size. Activation of suppressive genes by biofilm was sensitive to suppression by Jak inhibition. These results support an evolving paradigm that biofilm plays an active role in modulating immune responses, and suggest this occurs via production of a soluble vita-PAMP. Induction of T cell suppressive genes by S. aureus biofilm provides insights into mechanisms that suppress T cell immunity in PJI, and suggest that anti-PD-1 therapy that is modeled on immune checkpoint blockade for tumors may be beneficial in PJI.

immunology↗

bioRxiv2018

IFN-γ selectively suppresses a subset ofTLR4-activated genes and enhancers to potentiate M1-like macrophage polarization

Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-{gamma} and LPS. Synergistic activation of canonical inflammatory NF-{kappa}B target genes by IFN-{gamma} and LPS is well appreciated, but less is known about whether IFN-{gamma} negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-{gamma} selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-{gamma}-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-{gamma}-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-{gamma}. These findings reveal that IFN-{gamma} suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-{gamma} selectively inhibits TLR4-induced transcription.

immunology↗