The role of IL-23 receptor signaling in inflammation-mediated erosive autoimmune arthritis and bone remodeling

The IL-23/Th17 axis has been implicated in the development of autoimmune diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). RA and PsA are heterogeneous diseases with substantial burden on patients. Increasing evidence suggests that the IL-23 signaling pathway may be involved in the development of autoimmunity and erosive joint damage. IL-23 can act either directly or indirectly on bone forming osteoblasts as well as on bone resorbing osteoclasts. As IL-23 regulates the activity of cells of the bone, it is conceivable that in addition to inflammation-mediated joint erosion, IL-23 may play a role in physiological bone remodeling. In this review, we focus on the role of IL-23 in autoimmune arthritis in patients and murine models, and provide an overview of IL-23 producing and responding cells in autoimmune arthritic joints. In addition, we discuss the role of IL-23 on bone forming osteoblasts and bone resorbing osteoclasts regarding inflammation-mediated joint damage and bone remodeling. At last, we briefly discuss the clinical implications of targeting this pathway for joint damage and systemic bone loss in autoimmune arthritis

Dendritic cell-specific deletion of β-catenin results in fewer regulatory T-cells without exacerbating autoimmune collagen-induced arthritis

Dendritic cells (DCs) are professional antigen presenting cells that have the dual ability to stimulate immunity and maintain tolerance. However, the signalling pathways mediating tolerogenic DC function in vivo remain largely unknown. The β-catenin pathway has been suggested to promote a regulatory DC phenotype. The aim of this study was to unravel the role of β-catenin signalling to control DC function in the autoimmune collagen-induced arthritis model (CIA). Deletion of β-catenin specifically in DCs was achieved by crossing conditional knockout mice with a CD11c-Cre transgen

CD4+CCR6+ T cells, but not γδ T cells, are important for the IL-23R-dependent progression of antigen-induced inflammatory arthritis in mice

IL-23 plays an important role in the development of arthritis and the IL-23 receptor (IL-23R) is expressed on different types of T cells. However, it is not fully clear which IL-23R+ T cells are critical in driving T cell-mediated synovitis. We demonstrate, using knock-in IL-23R-GFP reporter (IL-23RGFP/+) mice, that CD4+CCR6+ T cells and γδ T cells, but not CD8+ T cells, express the IL-23R(GFP). During early arthritis, IL-23R(GFP)+CD4+CCR6+ T cells, but not IL-23R(GFP)+ γδ T cells, were present in the inflamed joints. IL-23RGFP/+ mice were bred as homozygotes to obtain IL-23RGFP/GFP (IL-23R deficient/IL-23R−/−) mice, which express GFP under the IL-23R promotor. Arthritis progression and joint damage were significantly milder in IL-23R−/− mice, which revealed less IL-17A+ cells in their lymphoid tissues. Surprisingly, IL-23R−/− mice had increased numbers of IL-23R(GFP)+CD4+CCR6+ and CCR7+CD4+CCR6+ T cells in their spleen compared to WT, and IL-23 suppressed CCR7 expression in vitro. However, IL-23R(GFP)+CD4+CCR6+ T cells were present in the synovium of IL-23R−/− mice at day 4. Finally, adoptive transfer experiments revealed that CD4+CCR6+ T cells and not γδ T cells drive arthritis progression. These data suggest that IL-23R-dependent T cell-mediated synovitis is dependent on CD4+CCR6+ T cells and not on γδ T cells

The role of IL-23 and CCR6+ memory T helper cells in healthy and inflammatory arthritis conditions

Interleukin 23 (IL-23) is a pro-inflammatory cytokine, which is secreted by activated dendritic cells and macrophages, which are located in peripheral tissues such as the intestinal mucosa, skin and the joints. Once secreted, IL-23 binds to the IL-23 receptor (IL-23R) on its target cells to induce the production of other pro-inflammatory cytokines, such as IL-17A, IL-22, TNFα. These cytokines can also stimulate the production of other pro-inflammatory cytokines, anti-microbial peptides and chemokines, for instance for control of infections. In addition to its contribution in fighting pathogens that can cause infections, IL-23 can also affect bone remodeling during physiological condition. This is made possible through (in)direct interactions of IL-23 with several immune and non-immune cells, such as osteoblasts (bone forming cells) and osteoclasts (bone resorbing cells).This thesis consists of two parts. In part I, we focused on the effects of IL-23/IL-23R signaling under healthy conditions on CCR6+ memory T helper (Th) cells, one of the target cells of IL-23, and the precursors of osteoclasts (chapter 4). Also, the role of IL-23R signaling was investigated in physiological bone remodeling (chapter 3). In part II, the focus was on the role of IL-23/IL-23R signaling and its target cells, the CCR6+ Th cells, during inflammatory arthritis (IA). Inflammatory arthritis is a broad term used for several conditions in which an abnormal immune response leads to joint inflammation. This thesis focuses on rheumatoid arthritis (RA) and psoriatic arthritis (PsA)<br/

The role of IL-23 and CCR6+ memory T helper cells in healthy and inflammatory arthritis conditions

Interleukin 23 (IL-23) is a pro-inflammatory cytokine, which is secreted by activated dendritic cells and macrophages, which are located in peripheral tissues such as the intestinal mucosa, skin and the joints. Once secreted, IL-23 binds to the IL-23 receptor (IL-23R) on its target cells to induce the production of other pro-inflammatory cytokines, such as IL-17A, IL-22, TNFα. These cytokines can also stimulate the production of other pro-inflammatory cytokines, anti-microbial peptides and chemokines, for instance for control of infections. In addition to its contribution in fighting pathogens that can cause infections, IL-23 can also affect bone remodeling during physiological condition. This is made possible through (in)direct interactions of IL-23 with several immune and non-immune cells, such as osteoblasts (bone forming cells) and osteoclasts (bone resorbing cells).This thesis consists of two parts. In part I, we focused on the effects of IL-23/IL-23R signaling under healthy conditions on CCR6+ memory T helper (Th) cells, one of the target cells of IL-23, and the precursors of osteoclasts (chapter 4). Also, the role of IL-23R signaling was investigated in physiological bone remodeling (chapter 3). In part II, the focus was on the role of IL-23/IL-23R signaling and its target cells, the CCR6+ Th cells, during inflammatory arthritis (IA). Inflammatory arthritis is a broad term used for several conditions in which an abnormal immune response leads to joint inflammation. This thesis focuses on rheumatoid arthritis (RA) and psoriatic arthritis (PsA)<br/

Characterizing memory T helper cells in patients with psoriasis, subclinical, or early psoriatic arthritis using a machine learning algorithm

Background: Psoriasis patients developing psoriatic arthritis (PsA) are thought to go through different phases. Understanding the underlying events in these phases is crucial to diagnose PsA early. Here, we have characterized the circulating memory T helper (Th) cells in psoriasis patients with or without arthralgia, psoriasis patients who developed PsA during follow-up (subclinical PsA), early PsA patients and healthy controls to elucidate their role in PsA development. Methods: We used peripheral blood mononuclear cells of sex and age-matched psoriasis patients included in Rotterdam Joint Skin study (n=22), early PsA patients included in Dutch South West Early Psoriatic Arthritis Cohort (DEPAR) (n=23) and healthy controls (HC; n=17). We profiled memory Th cell subsets with flow cytometry and used the machine learning algorithm FlowSOM to interpret the data. Results: Three of the 22 psoriasis patients developed PsA during 2-year follow-up. FlowSOM identified 12 clusters of memory Th cells, including Th1, Th2, Th17/22, and Th17.1 cells. All psoriasis and PsA patients had higher numbers of Th17/22 than healthy controls. Psoriasis patients without arthralgia had lower numbers of CCR6-CCR4+CXCR3+ memory Th cells and higher numbers of CCR6+CCR4-CXCR3-memory Th cells compared to HC. PsA patients had higher numbers of Th2 cells and CCR6+CCR4+CXCR3- cells, but lower numbers of CCR6+CCR4+CXCR3+ memory Th cells compared to HC. The number of CCR6+ Th17.1 cells negatively correlated with tender joint counts and the number of CCR6+ Th17 cells positively correlated with skin disease severity. Conclusions: Unsupervised clustering analysis revealed differences in circulating memory Th cells between psoriasis and PsA patients compared to HC; however, no specific subset was identified characterizing subclinical PsA patients

IL-23 receptor deficiency results in lower bone mass via indirect regulation of bone formation

The IL-23 receptor (IL-23R) signaling pathway has pleiotropic effects on the differentiation of osteoclasts and osteoblasts, since it can inhibit or stimulate these processes via different pathways. However, the potential role of this pathway in the regulation of bone homeostasis remains elusive. Therefore, we studied the role of IL-23R signaling in physiological bone remodeling using IL-23R deficient mice. Using µCT, we demonstrate that 7-week-old IL-23R−/− mice have similar bone mass as age matched littermate control mice. In contrast, 12-week-old IL-23R−/− mice have significantly lower trabecular and cortical bone mass, shorter femurs and more fragile bones. At the age of 26 weeks, there were no differences in trabecular bone mass and femur length, but most of cortical bone mass parameters remain significantly lower in IL-23R−/− mice. In vitro osteoclast differentiation and resorption capacity of 7- and 12-week-old IL-23R−/− mice are similar to WT. However, serum levels of the bone formation marker, PINP, are significantly lower in 12-week-old IL-23R−/− mice, but similar to WT at 7 and 26 weeks. Interestingly, Il23r gene expression was not detected in in vitro cultured osteoblasts, suggesting an indirect effect of IL-23R. In conclusion, IL-23R deficiency results in temporal and long-term changes in bone growth via regulation of bone formation