Biology subjects

Nijnik, A.

Publications and source records attributed to Nijnik, A..

5 recordsLinked to original sources

bioRxiv2026

Increased Expression and Altered Functional Activities of Immune Receptors TREM1, PD-L1, and Others on Hematopoietic Progenitor Cells in a Mouse Model of Rheumatoid Arthritis

Hematopoietic stem and progenitor cells (HSPCs) sustain the production of hundreds of billions of new cells per day to maintain our blood and immune system. In this process, HSPCs regulate the hematopoietic output by sensing and integrating diverse physiological cues. Thus, HSPCs express many receptors traditionally studied for their functions in the immune system, and this allows HSPCs to directly detect microbial compounds, endogenous danger signals, cytokines, and other inflammatory mediators. However, how the expression levels of such receptors on HSPCs change under chronic inflammation and how such changes alter HSPC functions and immune cell production remains unexplored. Working in a murine model of rheumatoid arthritis, we demonstrate the induction of microbial sensors TLR2 and CD14, orphan inflammatory receptor TREM1, and checkpoint receptor PD-L1 on HSPCs and particularly the myeloid progenitor cells in the arthritis-afflicted mice. Furthermore, we demonstrate that the stimulation of HSPCs through these receptors in culture can significantly alter the dynamics of cell expansion and differentiation, with distinct responses from HSPCs of arthritis-afflicted versus healthy control mice. We hypothesize that the induction and stimulation of HSPCs through these immune receptors under chronic inflammation may impact the output and functional properties of their immune cell progeny, positing HSPCs as central players in the pathogenic inflammatory responses of rheumatoid arthritis and potentially other chronic inflammatory diseases. HIGHLIGHTSO_LIHematopoietic progenitor cells in murine models of rheumatoid arthritis show an upregulation of immune receptors TREM1, PD-L1, TLR2, and CD14. C_LIO_LIStimulation of murine hematopoietic stem and progenitor cells through these receptors in culture alters the dynamics of their expansion and differentiation. C_LIO_LIIn such cultures, hematopoietic stem and progenitor cells from mice afflicted with rheumatoid arthritis show altered responses to stimulation as compared to healthy controls. C_LI

immunology↗

bioRxiv2026

Loss of MYSM1 deubiquitinase catalytic activity protects against MYC-driven B cell lymphoma via tumor intrinsic effects and indirect modulation of antitumor immunity

BackgroundMYC is an oncogenic transcription factor that is over-expressed, amplified, or otherwise dysregulated in over 50% of all cancers. This includes over 10% of diffuse large B-cell lymphomas (DLBCL), where MYC translocations are associated with a poor therapy response and inferior prognosis for the patients. However, because MYC lacks ligand-binding or catalytic domains, it is a highly challenging drug target, and there is a wide interest in novel approaches to inhibit MYC oncogenic functions. MYSM1 is a chromatin-binding deubiquitinase (DUB) that promotes gene expression by catalytically removing the histone H2AK119ub epigenetic mark. In recent work, we demonstrated that MYSM1 acts in cooperation with MYC to sustain the expression of oncogenic transcriptional programs in hematopoietic cells, identifying MYSM1 as a potential therapeutic target for MYC-driven malignancies. ResultsHere, we show for the first time that the loss of MYSM1 DUB catalytic activity, without the loss of MYSM1 protein expression, is sufficient to protect against MYC-driven lymphoma in murine models. We characterize the impact of MYSM1 loss-of-function on tumor cell physiology and on antitumor immunity, examining the tumor-intrinsic and the immune cell-mediated mechanisms involved in the protection against the disease. Leveraging human cancer genome databases, we provide first evidence linking MYSM1 loss-of-function to reduced fitness of human lymphoma cell lines in culture and to more favorable clinical outcomes in cancer patients. ConclusionsOverall, our studies support pharmacological inhibition of MYSM1 DUB catalytic function as a novel therapeutic strategy for MYC-driven lymphoma and potentially other cancers.

cancer biology↗

bioRxiv2025

Trained Immunity Affecting Dendritic Cell Differentiation and Function in Rheumatoid Arthritis

Rheumatoid arthritis affects [~]0.5-1% of the adult population and results in joint inflammation, chronic pain, and many systemic comorbidities. Immune and inflammatory tissue damage is the main pathogenic mechanism in rheumatoid arthritis, and involves the hyperactivation of both innate and adaptive immune systems. Trained immunity has become well established as an important feature of the innate immune system that allows the host to mount functionally altered immune responses based on their previous history of immune exposures, independently of the classical adaptive immunological memory. However, the role of trained immunity in systemic autoimmune and inflammatory disorders remains poorly understood. In the current work, we demonstrate that emergency myelopoiesis is induced in chronic rheumatoid arthritis in murine models and acts not only to enhance innate immune cell numbers but also to produce functionally altered innate immune cells. Such effects are cell-intrinsic to hematopoietic stem and progenitor cells (HSPCs) and persist independently of the inflammatory disease milieu. Importantly, these trained immunity mechanisms impact not only macrophages but also dendritic cells, which are the major antigen presenting cells that bridge the innate and adaptive immune responses. Trained dendritic cells show changes in global gene expression profiles, and significantly altered responses to recall immune stimulation and capacity for T cell activation. This study therefore represents the first demonstration of dendritic cell trained immunity in rheumatoid arthritis.

immunology↗

bioRxiv2025

Low Dose Methotrexate has Divergent Effects on Cycling and Resting Human Hematopoietic Stem and Progenitor Cells

Low dose methotrexate (LD-MTX) remains the gold standard in rheumatoid arthritis (RA) therapy. Multiple mechanisms on a variety of immune cells contribute to the anti-inflammatory effects of LD-MTX. Inflammatory signaling is deeply implicated in hematopoiesis by regulating hematopoietic stem and progenitor cell (HSPC) fate decisions; raising the question of whether HSPC are also modulated by LD-MTX. This is the first study to characterize the effects of LD-MTX on HSPC. CD34+ HSPC were isolated from healthy donors non-mobilized peripheral blood. Resting and/or cycling HSPCs were treated with LD-MTX [dose equivalent to that used in RA patients]. Flow cytometry was performed to assess HSPC viability, cell cycle, surface abundance of reduced folate carrier 1 (RFC1), proliferation, reactive oxygen species (ROS) levels, DNA double-strand breaks, p38 activation, and CD34+ subpopulations. HSPC clonogenicity was tested in colony-forming cell assays. Our results indicate that in cycling HSPC, membrane RFC1 is upregulated and, following LD-MTX treatment, they accumulate more intracellular MTX than resting HSPC. In cycling HSPC, LD-MTX inhibits HSPC expansion by promoting S-phase cell-cycle arrest, increases intracellular HSPC ROS levels and DNA damage, and reduces HSPC viability. Those effects involve the activation of the p38 MAPK pathway and are rescued by folinic acid. The effects of LD-MTX are more evident in CD34+CD38High progenitors. In non-cycling HSPC, LD-MTX also reduces the proliferative response while preserving their clonogenicity. In summary, HSPC uptake LD-MTX differentially according to their cycling state. In turn, LD-MTX results in reduced proliferation and the preservation of HSPC clonogenicity. Study Highlight QuestionsO_ST_ABSWhat is the current knowledge on the topic?C_ST_ABSO_LILow dose-methotrexate (LD-MTX) regulates the function of key cells involved in rheumatoid arthritis (RA) pathogenesis (e.g. T cells, macrophages, neutrophils, endothelial cells and fibroblast-like synoviocytes) and through the activation of multiple pathways contribute to the suppression of inflammation in RA. C_LIO_LIInflammatory signaling impacts hematopoiesis by regulating hematopoietic stem and progenitor cells (i.e. HSPC, CD34+ cells). C_LI What question did this study address?O_LIDoes LD-MTX modulate key functional properties of HSPC subpopulations (i.e. resting and/or cycling HSPCs) C_LI What does this study add to our knowledge?O_LIHSPC uptake LD-MTX differentially according to their cycling state. C_LIO_LICycling HSPC upregulate membrane RFC1 and uptake more MTX than resting HSPC with activation of the p38 MAPK pathway. This leads to inhibition of HSPC expansion, increased intracellular ROS levels and DNA damage, and reduced HSPC viability. C_LIO_LILD-MTX preserves the clonogenicity of non-cycling HSPC. C_LI How might this change clinical pharmacology or translational science?O_LIWe describe a novel mechanism of action of LD-MTX that extends its therapeutic effects from mature immune cells to the modulation of hematopoiesis. C_LI

immunology↗

bioRxiv2019

A loss-of-function mutation in Itgal contributes to the high susceptibility of Collaborative Cross strain CC042 to Salmonella infections

Salmonella are intracellular bacteria that are found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. They are one of the leading causes of foodborne infections and a major threat for human populations worldwide. Mouse models have been extensively used to model distinct aspects of the human Salmonella infections in vivo and have led to the identification of several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross strains to intravenous infection with Salmonella Typhimurium as a model of human systemic invasive infection. In this model, strain CC042 displayed extreme susceptibility with very high bacterial loads and mortality. CC042 mice showed lower spleen weight and decreased splenocyte numbers before and after infection, affecting mostly CD8+ T cells, B cells, and all myeloid populations. Uninfected mice also had lower thymus weight with reduced total number of thymocytes and double negative and (CD4+, CD8+) double positive thymocytes. Analysis of bone marrow resident hematopoietic progenitors showed a strong bias against lymphoid primed multipotent progenitors, which are the precursors of T, B and NK cells. An F2 cross between CC042 and C57BL/6N identified two significant QTLs on chromosome 7 (Stsl6 and Stsl7) with WSB-derived susceptible alleles. A private variant in the integrin alpha L (Itgal) gene is carried by CC042 in the Stsl7 QTL region. A quantitative complementation test confirmed the impact of Itgal loss of function in a (C57BL/6JxCC042)F1 background, but not in a C57BL/6J inbred background. These results further emphasize the utility of the Collaborative Cross to identify new host genetic variants controlling susceptibility to infections and improve our understanding of the function of the Itgal gene.\n\nAuthor summarySalmonella are one of the leading causes of foodborne infections and a major threat for human populations worldwide. Not all humans are equally susceptible to Salmonella infection. Some individuals will develop minor symptoms and recover while others develop severe illness and might die. Mouse models are used to study distinct aspects of human Salmonella infection in vivo. We used a new genetically diverse mouse population to investigate host susceptibility differences to Salmonella infection. We identified one mouse strain with an extreme susceptibility to infection characterized by very high bacterial loads and mortality. Mice of this strain had small thymus and spleen, two organs which are very important for producing a fully mature immune system. We showed that the strains immune response is impaired and that its extreme susceptibility to Salmonella infection is due to multiple genes defects. We identified a loss-of-function mutation in the Itgal gene (Integrin Subunit Alpha L) that plays a central role in the immune response to infection. This gene explains part of the susceptibility and other gene(s) involved remain to be identified. Our results emphasize how new genetically diverse animal models can lead to the identification of new host genetic variants controlling susceptibility to pathogens and improve our understanding of human infections.

immunology↗