Biology subjects

Chinenov, Y.

Publications and source records attributed to Chinenov, Y..

5 recordsLinked to original sources

bioRxiv2024

Opposing Regulation of TNF Responses and IL-1b+ Macrophages by PGE2-cAMP and IFN-g Signaling

IL-1{beta}-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory arthritis (ICI-arthritis), and pancreatic cancer and proposed to be pathogenic. In RA and pancreatic cancer IL-1{beta}+ macrophages express genes cooperatively induced by PGE2 and TNF signaling, but mechanisms that induce these cells and the extent to which they contribute to arthritic phenotypes are not known. In this study we used an integrated transcriptomic and epigenomic analysis in primary human monocytes to study PGE2-TNF crosstalk, and how it is regulated by IFN-{gamma}, as occurs in RA synovial macrophages. We identified a TNF + PGE2 (TP) induced gene expression signature that is enriched in a previously identified IL1{beta}+ RA monocytic subset defined by scRNAseq and includes genes in pathogenic IL-1, Notch and neutrophil chemokine pathways. A similar TP gene expression signature was apparent in an IL-1{beta}+ macrophage subset newly identified by scRNAseq in ICI-arthritis. Reference mapping revealed that ICI-arthritis myeloid cells map primarily onto four previously defined RA synovial monocytic clusters, and the TP signature extends beyond IL-1{beta}+ cells to subsets of adjacent clusters, suggestive of a new functional monocyte subset. TP signature genes are distinct from canonical inflammatory NF-{kappa}B target genes such as TNF, IL6 and IL12B and are activated by cooperation of PGE2-induced AP-1, CEBP and NR4A family transcription factors with TNF-induced NF-{kappa}B activity. Unexpectedly, IFN-{gamma} suppressed induction of AP-1, CEBP and NR4A activity to ablate induction of IL-1, Notch and neutrophil chemokine genes, while promoting expression of distinct inflammatory genes such as TNF and T cell chemokines like CXCL10. The opposing cross-regulation of PGE2 and IFN signaling in vitro was reflected in vivo in mutually exclusive expression of TP and IFN signatures in different cell clusters in RA and ICI-arthritis monocytes. These results reveal the basis for synergistic induction of inflammatory genes by PGE2 and TNF, and a novel regulatory axis whereby IFN-{gamma} and PGE2 oppose each other to determine the balance between two distinct TNF-induced inflammatory gene expression programs relevant for RA and ICI-arthritis.

immunology↗

bioRxiv2024

Mechanisms of Epigenomic and Functional Convergence Between Glucocorticoid and IL4-Driven Macrophage Programming

Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids, widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics that M2IL4 and M2GC transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets. This core homeostatic program is enacted by transcriptional effectors KLF4 and the GC receptor, whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, many of the M2IL4:M2GC-shared transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated phagocytic activity of both populations in vitro and macrophage tissue-repair properties in the murine colitis model in vivo. These findings provide a mechanistic framework for homeostatic macrophage programming by distinct signals, to better inform anti-inflammatory drug design.

immunology↗

bioRxiv2021

Type I interferon modulates Langerhans cell ADAM17 to promote photosensitivity in lupus

BackgroundThe autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure inflames skin. Beneficial effects of anifrolumab (anti-interferon /breceptor (anti-IFNAR)) on lupus skin disease support a pathogenic role for IFN-I, but mechanistic understanding is limited. We have shown that Langerhans cell (LC) dysfunction contributes to photosensitivity. Healthy LCs act via a disintegrin and metalloprotease 17 (ADAM17) to release epidermal growth factor receptor (EGFR) ligands that limit UVR-induced keratinocyte apoptosis and photosensitivity. However, LC ADAM17 activity is reduced in non-lesional lupus model skin, and data point to reduced LC-mediated protection in human lupus. Here, we asked about the role of the IFN-rich lupus skin environment in LC dysfunction and the implications of this regulation for photosensitivity. MethodsGene expression patterns in non-lesional skin from human lupus and multiple murine models were examined. We used MRL/lpr, B6.Sle1yaa, and imiquimod models of lupus in in vivo studies to assess the role of IFN-I in LC ADAM17 dysfunction and photosensitivity. ResultsWe show a shared IFN-rich environment in non-lesional skin across human and murine model systems, that IFN-I inhibits LC ADAM17 activity, and that anti-IFNAR in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17-dependent manners. Reactive oxygen species (ROS) can mediate ADAM17 activity, and we show reduced LC ROS expression in lupus models that is restored by anti-IFNAR. ConclusionsOur findings suggest that IFN-I promotes photosensitivity by causing LC ADAM17 dysfunction and that anifrolumab ameliorates lupus skin disease at least in part by restoring LC function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a mechanism of action for anifrolumab in lupus.

immunology↗

bioRxiv2021

Sex-specific differences in the function and differentiation of ABCsmark TLR7-driven immunopathogenesis

Sex differences characterize immune responses to viruses and autoimmune diseases like SLE. ABCs are an emerging population of CD11c+ T-bet+ B cells critical for antiviral responses and autoimmune disorders. DEF6 and SWAP70, are two homologous molecules whose combined absence in double-knock-out mice (DKOs) leads to a lupus syndrome in females marked by an accumulation of ABCs. Here we demonstrate that DKO ABCs exhibit sex-specific differences in their expansion, upregulation of an ISG signature, and further differentiation. BCR sequencing and fate mapping experiments reveal that DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c- effector populations with pathogenic and proinflammatory potential. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function, and differentiation of ABCs contributing to the sex-bias that accompanies TLR7-driven immunopathogenesis.

immunology↗

bioRxiv2020

Age-related Impairment of Implant Osseointegration is Associated with Immune Activation and Suppression of Angiogenic, Notch, and Wnt Pathways

The number of total joint replacements (TJRs) in the United States is increasing annually. Cementless implants are intended to improve upon traditional cemented implants by allowing bone growth directly on the surface to improve implant longevity. One major complication of TJR is implant loosening, which is related to deficient osseointegration in cementless TJRs. Although poor osseointegration in aged patients is typically attributed to decreased basal bone mass, little is known about the molecular pathways that compromise the growth of bone onto porous titanium implants. To identify the pathways important for osseointegration that are compromised by aging, we developed an approach for transcriptomic profiling of peri-implant tissue in young and aged mice using our murine model of osseointegration. Based on previous findings of changes of bone quality associated with aging, we hypothesized that aged mice have impaired activation of bone anabolic pathways at the bone-implant interface. We found that pathways most significantly downregulated in aged mice relative to young mice are related to angiogenic, Notch and Wnt signaling. Downregulation of these pathways is associated with markedly increased expression of inflammatory and immune genes at the bone-implant interface in aged mice. These results identify osseointegration pathways affected by aging and suggest that an increased inflammatory response in aged mice may compromise peri-implant bone healing. Targeting the Notch and Wnt pathways, promoting angiogenesis, or modulating the immune response at the peri-implant site may enhance osseointegration and improve the outcome of joint replacement in older patients.

immunology↗