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Emergency Myelopoiesis in Murine Arthritis Results in Cell-Intrinsic Changes in Dendritic Cell Development and Function

ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects up to 0.5-1% of the adult global population.. Immune and inflammatory tissue damage is the main pathogenic mechanism in RA, and involves a hyperactivation of both innate and adaptive immune systems. Trained immunity, an important feature of the innate immune system, 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, with the effects on monocyte and macrophage differentiation and function being most widely studied. We demonstrate that emergency myelopoiesis is induced in chronic rheumatoid arthritis in murine models and acts not only to enhance the counts but also to produce functionally altered innate immune cells. Such effects are cell-intrinsic affecting 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 professional antigen presenting cells, bridging the innate and adaptive immune responses. Such mechanisms result in changes in the global transcriptional profiles of dendritic cells, and significantly alter their 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE291186 | GEO | 2026/06/17

REPOSITORIES: GEO

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Project description:The pathogenesis of rheumatoid arthritis (RA) is complicated and involves both innate and adaptive immunity [5]. The innate immunity such as macrophages or fibroblast-like synoviocytes (FLS) in the synovium can generate inflammatory mediators, including TNF-α, IL-1, IL-6, IL-17, IFN-γ, and chemo kines that lead to synovial inflammation, bone erosion, and cartilage damage [6-8]. The IL-17 signaling mediates the autoantibody production in collagen-induced arthritis (CIA) model [9]. However, the treatment response with an anti-IL17 monoclonal antibody in RA patients shows a high degree of heterogeneity [10]. The inhibitors of the Janus kinase (JAK) pathway are approved for RA patients [11]. These data suggest that the targeted multiple cytokines through the JAK pathway are useful for RA treatment. Disturbance of type I IFNs (IFNs-I) signaling and production drive autoimmune development [12]. The presymptomatic RA patients display an increase of IFNs-I before the onset of symptoms [13]. The RA patients also show the elevation of IFN- α in the synovial fluid and high expression of IFNs-I regulated gene in peripheral blood mononuclear cells (PBMC) [14]. However, the role of IFNs-I in arthritis and bone homeostasis has suggested the accelerating effect of arthritis and bone damage. The interferon-alpha receptor knockout mice develop arthritis severity higher than wild-type mice in the model of antigen-induced arthritis [15]. IFNs-I also affects the bone homeostasis by inhibiting osteoclastogenesis via receptor activator of nuclear factor-kappa B (RANK) pathway, and reduction of c-FOS expression [16-18]. Therefore, the goal of RA treatment with antagonizing the IFNs-I pathway has to be optimized between efficacy and potentially adverse effect. STING is a cytosolic DNA sensor that initiates the production of IFNs-I. STING functions have been reported as both pro-inflammatory signaling and negative regulator against inflammation [19-21]. The mutation in exon 5 of the STING gene results in gain function leading to initiate inflammation and cause the Sting associated vasculopathy with onset in infancy (SAVI) [22]. Loss of STING function rescues DNaseII-deficient mice from lethality and polyarthritis [23]. However, Sting-deficient lupus mice (MRL/Lpr mice) show higher and earlier mortality than Sting-sufficient MRL/Lpr mice [24]. The pathology also shows lymphoid hypertrophy with a higher amount of macrophages and granulocytes infiltration, autoantibodies, and cytokine [24]. The objective of this study was to identify the role of STING in the pathogenesis of rheumatoid arthritis using collagen-induced arthritis (CIA) model as a representative model of the human RA.

Project description:Baker2013 - Cytokine Mediated Inflammation in Rheumatoid Arthritis This model by Baker M. 2013, describes the interaction between pro and anti-inflammatory cytokine signalling in rheumatoid arthritis. Using two ordinary differential equations, the first model [BIOMD0000000550] analyses bifurcation and describes different pathological states by altering inflammatory regulation parameters. The second model [BIOMD0000000549] includes the effect that ageing has on pro-inflammatory signalling, allowing for time-dependant properties and disease progression to be observed. The author also describes potential dosing for reversal of the disease state. This model is described in the article: Mathematical modelling of cytokine-mediated inflammation in rheumatoid arthritis. Baker M, Denman-Johnson S, Brook BS, Gaywood I, Owen MR. Math Med Biol 2013 Dec; 30(4): 311-337 Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease preferentially affecting the joints and leading, if untreated, to progressive joint damage and disability. Cytokines, a group of small inducible proteins, which act as intercellular messengers, are key regulators of the inflammation that characterizes RA. They can be classified into pro-inflammatory and anti-inflammatory groups. Numerous cytokines have been implicated in the regulation of RA with complex up and down regulatory interactions. This paper considers a two-variable model for the interactions between pro-inflammatory and anti-inflammatory cytokines, and demonstrates that mathematical modelling may be used to investigate the involvement of cytokines in the disease process. The model displays a range of possible behaviours, such as bistability and oscillations, which are strongly reminiscent of the behaviour of RA e.g. genetic susceptibility and remitting-relapsing disease. We also show that the dose regimen as well as the dose level are important factors in RA treatments. This model is hosted on BioModels Database and identified by: BIOMD0000000550. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Baker2013 - Cytokine Mediated Inflammation in Rheumatoid Arthritis - Age Dependant This model by Baker M. 2013, describes the interaction between pro and anti-inflammatory cytokine signalling in rheumatoid arthritis. Using two ordinary differential equations, the first model [BIOMD0000000550] analyses bifurcation and describes different pathological states by altering inflammatory regulation parameters. The second model [BIOMD0000000549] includes the effect that ageing has on pro-inflammatory signalling, allowing for time-dependant properties and disease progression to be observed. The author also describes potential dosing for reversal of the disease state. This model is described in the article: Mathematical modelling of cytokine-mediated inflammation in rheumatoid arthritis. Baker M, Denman-Johnson S, Brook BS, Gaywood I, Owen MR. Math Med Biol 2013 Dec; 30(4): 311-337 Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease preferentially affecting the joints and leading, if untreated, to progressive joint damage and disability. Cytokines, a group of small inducible proteins, which act as intercellular messengers, are key regulators of the inflammation that characterizes RA. They can be classified into pro-inflammatory and anti-inflammatory groups. Numerous cytokines have been implicated in the regulation of RA with complex up and down regulatory interactions. This paper considers a two-variable model for the interactions between pro-inflammatory and anti-inflammatory cytokines, and demonstrates that mathematical modelling may be used to investigate the involvement of cytokines in the disease process. The model displays a range of possible behaviours, such as bistability and oscillations, which are strongly reminiscent of the behaviour of RA e.g. genetic susceptibility and remitting-relapsing disease. We also show that the dose regimen as well as the dose level are important factors in RA treatments. This model is hosted on BioModels Database and identified by: BIOMD0000000549. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Emergency Myelopoiesis in Murine Arthritis Results in Cell-Intrinsic Changes in Dendritic Cell Development and Function

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