Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by local and systemic inflammation. The complex interplay between immune cells and soluble mediators leads to the induction and perpetuation of aberrant inflammatory and autoimmune responses. The research carried out in the last year in the field of RA enabled the identification of new mechanisms involved in the pathogenesis of the disease and therefore unmasked new potential therapeutic targets. In this review article we summarised the new insights into RA pathogenesis from original research articles published in the last year. 

Pathogenesis of rheumatoid arthritis: one year in review 2023.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent articular inflammation and joint damage. RA was first described over 200 years ago; however, its etiology and pathophysiology remain insufficiently understood. The current treatment of RA is mainly empirical or based on the current understanding of etiology with limited efficacy and/or substantial side effects. Thus, the development of safer and more potent therapeutics, validated and optimized in experimental models, is urgently required. To improve the transition from bench to bedside, researchers must carefully select the appropriate experimental models as well as draw the right conclusions. Here, we summarize the establishment, pathological features, potential mechanisms, advantages, and limitations of the currently available RA models. The aim of the review is to help researchers better understand available RA models; discuss future trends in RA model development, which can help highlight new translational and human‐based avenues in RA research.

Advances in experimental models of rheumatoid arthritis

Circulating PCSK9 relates to aggravated disease activity, Th17/Treg imbalance, and predicts treatment outcome of conventional synthetic DMARDs in rheumatoid arthritis patients

Interleukin (IL)-3 has long been known for its hematopoietic properties. However, recent evidence has expanded our understanding of IL-3 function by identifying IL-3 as a critical orchestrator of inflammation in a wide array of diseases. Depending on the type of disease, the course of inflammation, the cell or the tissue involved, IL-3 promotes either pathologic inflammation or its resolution. Here, we describe the cell-specific functions of IL-3 and summarize its role in diseases. We discuss the current treatments targeting IL-3 or its receptor, and highlight the potential and the limitations of targeting IL-3 in clinics. 

IL-3: key orchestrator of inflammation

Differential Regulation of Immune-Related Genes in the Developing Heart.

IL‐17‐producing Th17 cells play an important role in pathogenesis of rheumatoid arthritis (RA). Aberrant immune activation due to an imbalance between Th17 and regulatory T (Treg) cells is associated with the development of RA and other autoimmune diseases. Targeting pathogenic Th17 cells and their associated molecules is emerging as a promising strategy to treat and reverse RA. Here, we demonstrate that IL‐3 inhibits the differentiation of Th17 cells and promotes the development of Treg cells in IL‐2‐dependent manner. In IL‐2 KO mice, we observed that IL‐3 has no effect on differentiation of both Th17 and Treg cells. In addition, IL‐3 decreases pathogenic IL‐17A+TNF‐α+, IL‐17A+IFN‐γ+ and IL‐23R+ Th17 cells, secretion of GM‐CSF and IFN‐γ, and osteoclastogenesis when presented in the culture together with Th17 polarizing cytokines. Mechanistically, IL‐3 regulates the development of Th17 cells through the inhibition of STAT3 phosphorylation. IL‐3 treatment significantly decreases the pathogenic Th17 cell responses and arthritic scores in the mouse model of RA. Importantly, IL‐3 inhibits the differentiation of human Th17 cells. Thus, our results suggest a novel therapeutic role of IL‐3 in the regulation of Th17 cell‐mediated pathophysiology of RA.

IL‐3 regulates the differentiation of pathogenic Th17 cells

In inflammatory bone loss disorders, such as rheumatoid arthritis and post-menopausal osteoporosis, TNF-α is an important effector cytokine that promotes osteoclastogenesis and inhibits osteoblastogenesis. Currently, clinical interventions primarily include anti-osteoclastic agents to prevent bone loss, however, anabolic agents are scarce and there’s an utmost need. Previously, IL- 3 has been shown to enhance osteogenic differentiation of human bone marrow-derived mesenchymal stem cells in vitro. However, its role remains unclear in inflammatory pathologies, where TNF-α negatively impacts osteoblast differentiation. This study aims to investigate IL- 3’s impact on osteogenic differentiation process under the negative influence of TNF-α. Calvarial pre-osteoblasts were isolated from BALB/c mice pups and in vitro osteoblast differentiation was performed as per established protocols. TNF-α was used as a negative regulator of osteoblast differentiation and the effect of IL- 3 on this differentiation was studied by assessing matrix mineralization using Alizarin red S staining. Osteoblast differentiation markers, including, alkaline phosphatase and osteocalcin were evaluated using qPCR. ALP activity was measured using the pNPP colorimetric assay. Furthermore, Western blotting was employed to deduce the mechanism(s) of IL- 3 action on TNF-α-induced-inhibition of osteoblast differentiation. Alizarin red S staining revealed that IL- 3 priming protects pre-osteoblasts from TNF-α-induced-inhibition of osteoblast differentiation and that this protective effect is irreversible. Mechanistically, IL- 3 pretreatment suppresses TNF- α-induced activation of NF-κB/SMURF1 axis thus preventing β-CATENIN degradation, which drives osteogenic gene expression. Priming mouse pre-osteoblasts with IL- 3 prevents TNF-α-induced of osteoblast differentiation in vitro, and, thus, could be a novel candidate in the treatment of inflammatory bone loss disorders.

Priming of mouse pre-osteoblasts with Interleukin-3 attenuates TNF-α-induced-inhibition of osteoblast differentiation

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IL‐3 regulates the differentiation of pathogenic Th17 cells

Priming of mouse pre-osteoblasts with Interleukin-3 attenuates TNF-α-induced-inhibition of osteoblast differentiation